Small molecule modulators of the androgen receptor

ABSTRACT

Provided herein are compounds useful for modulating the activity of an androgen receptor, or a variant thereof, and related compositions and methods. Compounds of the invention are useful for antagonizing the androgen receptor splice variant AR-v7, and for the treatment of castration-resistant prostate cancer.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §§ 120 and 365(c) toand is a continuation of international PCT Application,PCT/US2018/044204, filed Jul. 27, 2018, which claims priority under 35U.S.C. § 119(e) to U.S. Provisional Application, U.S. Ser. No.62/538,471, filed Jul. 28, 2017, each of which is incorporated herein byreference.

GOVERNMENT SUPPORT

This invention was made with government support under grant number. P30CA014051 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND

Prostate cancer is the second leading cause of cancer-related mortalityof men in the United States according to the American Cancer Society.(1)A contributing factor is that tumors develop resistance to currenttreatments especially in therapies that involve targeting the androgenreceptor (AR). Treatments generally rely upon continual androgendeprivation therapy via direct AR antagonism (enzalutimde, bicalutamide)or decrease in adrenal androgen production (abiraterone acetate).However, acquired resistance to these treatments potentially leads tocastration-resistant prostate cancer (CRPC) and an overall death rate of1 in 38 men diagnosed with prostate cancer.(2, 3) Studies of CRPCdemonstrated that despite low levels of circulating androgens,AR-mediated gene expression is often maintained by AR splice variants(AR-vs) that do not rely on androgen signaling.(4) Due to variations intheir C-terminus, these AR-vs are commonly constitutively active andeffectively mimic full-length AR (AR-FL) in their ability totransactivate androgen response elements (ARE) without androgenstimulation.(5) There are currently no FDA-approved drugs that targetAR-vs leaving patients with CRPC with little or no option for treatment.

The full-length androgen receptor (AR-FL) is a steroid receptortranscription factor composed of an N-terminal domain (NTD), a DNAbinding domain (DBD), and a C-terminal domain (CTD) consisting of ahinge region and a ligand binding domain (LBD).(6) In order for AR-FL totranslocate to the nucleus for gene expression, androgens bind to theLBD inducing a structural change that exposes the nuclear localizationsignal (NLS) thereby initiating importation into the nucleus. Drugs suchas enzalutamide target the LBD and thus, prevent nuclear translocationand AR-mediated gene expression. However, AR-vs arise from alternativesplicing of the AR gene by insertion of “intronic” cryptic exonsdownstream of exons encoding the DNA-binding domain, thereby preventingligand binding domain (LBD) incorporation.(7-9) Unfortunately, AR-vshave a basal level of nuclear localization and remain capable oftranscriptional activity, even with the loss of the LBD.(10) This lossof LBD, in turn, provides a resistance pathway for current drugregimens.

Of the 15 known AR-v isoforms, AR-v7 is the most widely identified andclinically important variant in prostate cancer.(11) It is characterizedby an unperturbed NTD and DBD with a portion of the NLS and a unique16-amino acid sequence in its CTD derived from a cryptic exonincorporation.(7, 8) AR-v7 is constitutively active in the absence ofandrogens, can form homodimers and heterodimers with AR-FL promotingcanonical AR-mediated gene expression, and also supports an expressionprofile unique to that of AR-FL, which includes prostate cancer relevantoncogene AKT1.(8, 12, 13) According to Haber and co-workers whoconducted single-cell RNA-seq analysis on circulating tumor cells(CTCs), approximately 43% of CTCs (73 cells) from 11 patients with CRPCexpressed at least one type of AR splice variant.(14) Eight out of 11patients expressed AR-v7, and 8 out of 11 also expressed ARv567es(AR-v12).(14) Another recent study by Dai, Ye, and coworkers,demonstrated a significantly higher rate of AR-v7 expression in primarytumor cells derived from metastatic prostate cancer and CRPC patientsover patients with localized prostate cancer.(15) As a result, theydirectly correlated higher AR-v7 expression to shorter survivallikelihood in CRPC (p<0.001). AR-v7 is a clear avenue for resistance andCRPC persistence.

AR-v7 expression is an identified resistance pathway for continualAR-mediated gene expression that is commonly found in metastaticprostate cancer. Currently, there are no therapeutics specificallytargeting AR-v7, thus leaving patients who present AR-v7 in CRPC withlittle or no options for treatment. Current androgen deprivationtherapies rely on drugs such as abiraterone acetate or enzalutamide thateither target the LBD of AR directly or alter adrenal androgenproduction. Because the majority of functional splice variants lack theligand binding domain and are constitutively active, these frontlinemedications are rendered useless.

Due to the importance of AR-v7 in CRPC and metastatic CRPC, thereremains a need for small molecules capable of binding AR-v7.

SUMMARY

To meet this need, compounds binding to AR-v7 were identified using thecombination of a small molecule microarray (SMM) screen of 50,000compounds, qPCR, and reporter assays. The SMM was screened against afunctional AR-truncate composed of the NTD and DBD (exons 1-3) andtherefore targeting these domains specifically. Candidate compounds werefurther evaluated in a series of assays designed to show specificity toAR-sensitive cell lines.

Compounds (1) and (2), shown below, were found to bind to AR-v7.Compound (1) demonstrated a promising IC₅₀ of 5.43 μM in an LNCaPreporter assay. Compound (2) displayed a relatively similar IC₅₀ of 6.86μM in an LNCaP reporter assay.

Accordingly, in one aspect, provided herein is a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted heterocyclyl or optionally substitutedheteroaryl;

L and L₁, independently, are absent, optionally substituted C₁₋₆aliphatic, or optionally substituted C₁₋₆ heteroaliphatic;

Q is hydrogen, halogen, —CN, —NO₂, —R^(a), —OH, —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)N(R^(a))₂, —NH₂, —N(R^(a))₂, —NC(O)R^(a),—NC(O)OR^(a), or —NC(O)N(R^(a))₂;

each of occurrence of R^(a), independently, is optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R₁ is optionally substituted aliphatic, optionally substitutedheteroaliphatic, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

R₂ is hydrogen, optionally substituted aliphatic, or optionallysubstituted heteroaliphatic;

X₁ and X₂, independently, are hydrogen, halogen, —OH, or optionallysubstituted aliphatic, or X₁ and X₂ are taken together to form an oxo(═O) group; and

Q and L, Q and L₁, Q and R₂ or Q and X₁ may combine to form a ring.

In an embodiment, the compound of Formula (I) is selected from Formulae(IA), (IB), (IC), (ID) and (IE), and pharmaceutically acceptable saltsthereof:

In an embodiment, the compound of Formula (I) has the structure ofFormula (IF)

or a pharmaceutically acceptable salt thereof, wherein:

L is absent, optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic;

each occurrence of R is independently halogen, —CN, —NO₂, —R^(a), —OH,—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(a))₂, —NH₂, —N(R^(a))₂,—NC(O)R^(a), —NC(O)OR^(a), or —NC(O)N(R^(a))₂;

each occurrence of R^(a) is independently optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R₁ is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

R₂ is hydrogen, optionally substituted aliphatic, or optionallysubstituted heteroaliphatic;

Z₁ and Z₂ are independently absent, C₁₋₂ alkylene, or

provided that only one of Z₁ and Z₂ is

R₃ is optionally substituted aliphatic, optionally substitutedheteroaliphatic, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is 0-3.

In certain embodiments, the compound of Formula (I) is notN-(2-((1S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)ethyl)-3-((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)benzamideor a stereoisomer thereof. In a particular embodiment, the compound ofFormula (I) is not compound (1).

In certain embodiments, Formula (IF) is selected from Formulae (IF-a),(IF-b), (IF-c), (IF-d), and (IF-e):

In an embodiment, Formula (IF) is selected from Formulae (IF-a3),(IF-a4), (IF-b3), (IF-b4), (IF-c3), (IF-c4), (IF-d3), (IF-d4), (IF-e3),and (IF-e4):

In another aspect, provided herein is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

L₁ is absent, optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic;

L₂ is absent, optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic;

X is —O—, —S— or —N(R)—;

R is hydrogen or optionally substituted alkyl;

Q₁, Q₂, and Q₃, independently, are ═N— or ═C(R₁)—;

R₁ is hydrogen, halogen, —CN, —NO₂, —R^(a), —OH, —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)N(R^(a))₂, —NH₂, —N(R^(a))₂, —NC(O)R^(a),—NC(O)OR^(a), or —NC(O)N(R^(a))₂;

each occurrence of R^(a) is independently optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R₂ is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

R₃ is optionally substituted alkyl or optionally substituted cycloalkyl;

R₄ is hydrogen or optionally substituted alkyl; and

R₅ is optionally substituted aryl or optionally substituted heteroaryl.

In certain embodiments, the compound of Formula (II) is not4-((((1R,4R)-bicyclo[2.2.1]hept-5-en-2-yl)methyl)amino)-N,5-dimethyl-N-(quinolin-5-ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide,or a stereoisomer thereof. In a particular embodiment, the compound ofFormula (II) is not compound (2).

In an embodiment, the compound of Formula (II) has a structure selectedfrom Formulae (IIA), (IIB), (IIC), and (IID), and pharmaceuticallyacceptable salts thereof:

In a particular embodiment, the compound Formula (II) has the structureof Formula (IIA), or a pharmaceutically acceptable salt thereof:

wherein:

L₁ is absent, optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic;

L₂ is absent, optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic;

X is —O—, —S— or —N(R)—;

R is hydrogen or optionally substituted alkyl;

R₁ is halogen, —CN, —NO₂, —R^(a), —OH, —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)N(R^(a))₂, —NH₂, —N(R^(a))₂, —NC(O)R^(a),—NC(O)OR^(a), or —NC(O)N(R^(a))₂; wherein

each occurrence of R^(a) is independently optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R₂ is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

R₃ is optionally substituted alkyl or optionally substituted cycloalkyl;

R₄ is hydrogen or optionally substituted alkyl; and

R₅ is optionally substituted aryl or optionally substituted heteroaryl.In another aspect, provided herein is a pharmaceutical compositioncomprising a compound of the invention, and a pharmaceuticallyacceptable carrier or diluent.

In another aspect, provided herein is a method of modulating theexpression of a gene in a subject, wherein the gene expression ismediated by an androgen receptor, comprising administering to thesubject a compound of the invention.

In another aspect, provided herein is a method of modulating theexpression of a gene, wherein the gene expression is mediated by anandrogen receptor, comprising exposing the androgen receptor to acompound of the invention.

In another aspect, provided herein is a method of modulating theexpression of a gene, wherein the gene expression is mediated by anandrogen receptor, comprising contacting the androgen receptor with acompound of the invention.

In another aspect, provided herein is a method of modulating androgenreceptor function, comprising exposing the androgen receptor to acompound of the invention.

In another aspect, provided herein is a method of modulating androgenreceptor function in a subject, comprising administering to the subjecta compound of the invention.

In another aspect, provided herein is a method of modulating androgenreceptor function, comprising contacting the androgen receptor with acompound of the invention.

In another aspect, provided herein is a method of treating prostatecancer in a subject in need of such treatment comprising administeringto the subject a compound of the invention, or a pharmaceuticalcomposition thereof.

The details of certain embodiments of the invention are set forth in theDetailed Description of Certain Embodiments, as described below. Otherfeatures, objects, and advantages of the invention will be apparent fromthe Definitions, Examples, Figures, and Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The invention additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

In a formula,

is a single bond where the stereochemistry of the moieties immediatelyattached thereto is not specified, --- is absent or a single bond, and

or

is a single or double bond.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, replacement of ¹⁹F with ¹⁸F, or the replacement of a carbon bya ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure.Such compounds are useful, for example, as analytical tools or probes inbiological assays.

When a range of values is listed, it is intended to encompass each valueand subrange within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclicgroups. Likewise, the term “heteroaliphatic” refers to heteroalkyl,heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certainembodiments, the alkyl group is a substituted C₁₋₁₀ alkyl (such assubstituted C₁₋₆ alkyl, e.g., —CH₂F, —CHF₂, —CF₃ or benzyl (Bn)).

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl,and refers to an alkyl group wherein all of the hydrogen atoms areindependently replaced by a halogen, e.g., fluoro, bromo, chloro, oriodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms(“C₁₋₈ haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6carbon atoms (“C₁₋₆ haloalkyl”). In some embodiments, the haloalkylmoiety has 1 to 4 carbon atoms (“C₁₋₄ haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 3 carbon atoms (“C₁₋₃ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C₁₋₂haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atomsare replaced with fluoro to provide a perfluoroalkyl group. In someembodiments, all of the haloalkyl hydrogen atoms are replaced withchloro to provide a “perchloroalkyl” group. Examples of haloalkyl groupsinclude —CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

The term “heteroalkyl” refers to an alkyl group, which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry is not specified (e.g., —CH═CHCH₃,

may be in the (E)- or (Z)-configuration.

The term “heteroalkenyl” refers to an alkenyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkenylgroup refers to a group having from 2 to 10 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkenyl”). In some embodiments, a heteroalkenyl group has2 to 9 carbon atoms at least one double bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 8 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbonatoms, at least one double bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbonatoms, at least one double bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”).In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, atleast one double bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

The term “heteroalkynyl” refers to an alkynyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynylgroup refers to a group having from 2 to 10 carbon atoms, at least onetriple bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkynyl”). In some embodiments, a heteroalkynyl group has2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbonatoms, at least one triple bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbonatoms, at least one triple bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”).In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, atleast one triple bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl(C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) andcyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) andcyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₄ cycloalkyl. In certain embodiments, thecarbocyclyl includes 0, 1, or 2 C═C double bonds in the carbocyclic ringsystem, as valency permits.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl. In certain embodiments, the heterocyclyl issubstituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl,wherein 1, 2, or 3 atoms in the heterocyclic ring system areindependently oxygen, nitrogen, or sulfur, as valency permits.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 3 heteroatoms include, withoutlimitation, triazinyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14 r electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by an aryl group, wherein the point of attachment is on thealkyl moiety.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14 t electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl). In certain embodiments, the heteroaryl is substituted orunsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3,or 4 atoms in the heteroaryl ring system are independently oxygen,nitrogen, or sulfur. In certain embodiments, the heteroaryl issubstituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl,wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system areindependently oxygen, nitrogen, or sulfur.

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by a heteroaryl group, wherein the point of attachment is onthe alkyl moiety.

The term “unsaturated bond” refers to a double or triple bond.

The term “unsaturated” or “partially unsaturated” refers to a moietythat includes at least one double or triple bond.

The term “saturated” refers to a moiety that does not contain a doubleor triple bond, i.e., the moiety only contains single bonds.

Affixing the suffix “-ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl groups are optionally substituted. “Optionallysubstituted” refers to a group which may be substituted or unsubstituted(e.g., “substituted” or “unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” heteroalkyl, “substituted” or“unsubstituted” heteroalkenyl, “substituted” or “unsubstituted”heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted” means that at least onehydrogen present on a group is replaced with a permissible substituent,e.g., a substituent which upon substitution results in a stablecompound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, and includes any of thesubstituents described herein that results in the formation of a stablecompound. The present invention contemplates any and all suchcombinations in order to arrive at a stable compound. For purposes ofthis invention, heteroatoms such as nitrogen may have hydrogensubstituents and/or any suitable substituent as described herein whichsatisfy the valencies of the heteroatoms and results in the formation ofa stable moiety. The invention is not intended to be limited in anymanner by the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₄ aryl, and 5-14membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(a) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃₊X, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R)₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminalR^(dd) substituents can be joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂,—SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X is a counterion.

In certain embodiments, the carbon atom substituents are independentlyhalogen, substituted or unsubstituted C₁₋₆ alkyl, —OR^(aa), —SR^(aa),—N(R^(bb))₂, —CN, —SCN, —NO₂, —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), or —NR^(bb)C(═O)N(R^(bb))₂. Incertain embodiments, the carbon atom substituents are independentlyhalogen, substituted or unsubstituted C₁₋₆ alkyl, —OR^(aa), —SR^(aa),—N(R^(bb))₂, —CN, —SCN, or —NO₂.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein.

The term “thiol” or “thio” refers to the group —SH. The term“substituted thiol” or “substituted thio,” by extension, refers to athiol group wherein the sulfur atom directly attached to the parentmolecule is substituted with a group other than hydrogen, and includesgroups selected from —SR^(aa), —S═SR^(cc), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa), wherein R^(a) andR^(cc) are as defined herein.

The term “amino” refers to the group —NH₂. The term “substituted amino,”by extension, refers to a monosubstituted amino, a disubstituted amino,or a trisubstituted amino. In certain embodiments, the “substitutedamino” is a monosubstituted amino or a disubstituted amino group.

The term “carbonyl” refers a group wherein the carbon directly attachedto the parent molecule is sp² hybridized, and is substituted with anoxygen, nitrogen or sulfur atom, e.g., a group selected from ketones(—C(═O)R^(aa)), carboxylic acids (—CO₂H), aldehydes (—CHO), esters(—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)), amides (—C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), and imines(—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa)), —C(═NR^(bb))N(R^(bb))₂),wherein R^(a) and R^(bb) are as defined herein.

The term “silyl” refers to the group —Si(R^(aa))₃, wherein R^(a) is asdefined herein.

The term “boronyl” refers to boranes, boronic acids, boronic esters,borinic acids, and borinic esters, e.g., boronyl groups of the formula—B(R^(aa))₂, —B(OR^(cc))₂, and —BR^(aa)(OR^(cc)), wherein R^(aa) andR^(cc) are as defined herein.

The term “oxo” refers to the group ═O, and the term “thiooxo” refers tothe group ═S.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(aa), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamante, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g., —S(═O)₂R)include, but are not limited to, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, co-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material may be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. The salts can be prepared in situ during the finalisolation and purification of the compounds of the invention, orseparately by reacting a free base or free acid function with a suitablereagent, as described generally below. For example, a free base functioncan be reacted with a suitable acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may, include metal salts such as alkali metalsalts, e.g. sodium or potassium salts; and alkaline earth metal salts,e.g. calcium or magnesium salts. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

Additionally, as used herein, the term “pharmaceutically acceptableester” refers to esters that hydrolyze in vivo and include those thatbreak down readily in the human body to leave the parent compound or asalt thereof. Suitable ester groups include, for example, those derivedfrom pharmaceutically acceptable aliphatic carboxylic acids,particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, inwhich each alkyl or alkenyl moeity advantageously has not more than 6carbon atoms. Examples of particular esters include formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

Furthermore, the term “pharmaceutically acceptable prodrugs” as usedherein refers to those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the issues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” refers tocompounds that are rapidly transformed in vivo to yield the parentcompound of the above formula, for example by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418and Journal of Pharmaceutical Science, 66, 2 (1977), each of which isincorporated herein by reference in its entirety.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the patient such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the patient. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes anyand all coatings, antibacterial and antifungal agents, and absorptiondelaying agents, and the like that are compatible with the activity ofthe compound useful within the invention, and are physiologicallyacceptable to the patient. Supplementary active compounds may also beincorporated into the compositions. The “pharmaceutically acceptablecarrier” may further include a pharmaceutically acceptable salt of thecompound useful within the invention. Other additional ingredients thatmay be included in the pharmaceutical compositions used in the practiceof the invention are known in the art and described, for example inRemington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co.,1985, Easton, Pa.), which is incorporated herein by reference.

The term “small molecule” refers to molecules, whethernaturally-occurring or artificially created (e.g., via chemicalsynthesis) that have a relatively low molecular weight. Typically, asmall molecule is an organic compound (i.e., it contains carbon). Thesmall molecule may contain multiple carbon-carbon bonds, stereocenters,and other functional groups (e.g., amines, hydroxyl, carbonyls, andheterocyclic rings, etc.). In certain embodiments, the molecular weightof a small molecule is not more than about 1,000 g/mol, not more thanabout 900 g/mol, not more than about 800 g/mol, not more than about 700g/mol, not more than about 600 g/mol, not more than about 500 g/mol, notmore than about 400 g/mol, not more than about 300 g/mol, not more thanabout 200 g/mol, or not more than about 100 g/mol. In certainembodiments, the molecular weight of a small molecule is at least about100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at leastabout 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, atleast about 700 g/mol, at least about 800 g/mol, or at least about 900g/mol, or at least about 1,000 g/mol. Combinations of the above ranges(e.g., at least about 200 g/mol and not more than about 500 g/mol) arealso possible. In certain embodiments, the small molecule is atherapeutically active agent such as a drug (e.g., a molecule approvedby the U.S. Food and Drug Administration as provided in the Code ofFederal Regulations (C.F.R.)). The small molecule may also be complexedwith one or more metal atoms and/or metal ions. In this instance, thesmall molecule is also referred to as a “small organometallic molecule.”Preferred small molecules are biologically active in that they produce abiological effect in animals, preferably mammals, more preferablyhumans. Small molecules include, but are not limited to, radionuclidesand imaging agents. In certain embodiments, the small molecule is adrug. Preferably, though not necessarily, the drug is one that hasalready been deemed safe and effective for use in humans or animals bythe appropriate governmental agency or regulatory body. For example,drugs approved for human use are listed by the FDA under 21 C.F.R. §§330.5, 331 through 361, and 440 through 460, incorporated herein byreference; drugs for veterinary use are listed by the FDA under 21C.F.R. §§ 500 through 589, incorporated herein by reference. All listeddrugs are considered acceptable for use in accordance with the presentinvention.

As used herein, “mediate” refers to the action of a compound (e.g., asmall molecule, a gene, or a protein, such as a receptor or enzyme),whereby such action brings about, or contributes to, an effect.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, andautoimmune diseases.

The terms “deregulated” or “deregulation” refer to a state or conditionwherein the regulation of a gene or protein has been altered abrogatedsuch that the level or activity of the gene product is altered ormodified.

The terms “dysregulated” or “dysregulation” refer to a dysfunctionallevel or activity of a gene product, which may be associated with anundesirable condition or conditions.

The term “gene” refers to a nucleic acid fragment that expresses aprotein, including regulatory sequences preceding (5′ non-codingsequences) and following (3′ non-coding sequences) the coding sequence.“Native gene” refers to a gene as found in nature with its ownregulatory sequences. “Chimeric gene” or “chimeric construct” refers toany gene or a construct, not a native gene, comprising regulatory andcoding sequences that are not found together in nature. Accordingly, achimeric gene or chimeric construct may comprise regulatory sequencesand coding sequences that are derived from different sources, orregulatory sequences and coding sequences derived from the same source,but arranged in a manner different than that found in nature.“Endogenous gene” refers to a native gene in its natural location in thegenome of an organism. A “foreign” gene refers to a gene not normallyfound in the host organism, but which is introduced into the hostorganism by gene transfer. Foreign genes can comprise native genesinserted into a non-native organism, or chimeric genes. A “transgene” isa gene that has been introduced into the genome by a transformationprocedure.

The term “gene product” (also referred to herein as “gene expressionproduct” or “expression product”) encompasses products resulting fromexpression of a gene, such as RNA transcribed from a gene andpolypeptides arising from translation of such RNA. It will beappreciated that certain gene products may undergo processing ormodification, e.g., in a cell. For example, RNA transcripts may bespliced, polyadenylated, etc., prior to mRNA translation, and/orpolypeptides may undergo co-translational or post-translationalprocessing such as removal of secretion signal sequences, removal oforganelle targeting sequences, or modifications such as phosphorylation,fatty acylation, etc. The term “gene product” encompasses such processedor modified forms. Genomic, mRNA, polypeptide sequences from a varietyof species, including human, are known in the art and are available inpublicly accessible databases such as those available at the NationalCenter for Biotechnology Information (www.ncbi.nih.gov) or UniversalProtein Resource (www.uniprot.org). Databases include, e.g., GenBank,RefSeq, Gene, UniProtKB/SwissProt, UniProtKB/Trembl, and the like. Ingeneral, sequences, e.g., mRNA and polypeptide sequences, in the NCBIReference Sequence database may be used as gene product sequences for agene of interest. It will be appreciated that multiple alleles of a genemay exist among individuals of the same species. For example,differences in one or more nucleotides (e.g., up to about 1%, 2%, 3-5%of the nucleotides) of the nucleic acids encoding a particular proteinmay exist among individuals of a given species. Due to the degeneracy ofthe genetic code, such variations often do not alter the encoded aminoacid sequence, although DNA polymorphisms that lead to changes in thesequence of the encoded proteins can exist. Examples of polymorphicvariants can be found in, e.g., the Single Nucleotide PolymorphismDatabase (dbSNP), available at the NCBI website atwww.ncbi.nlm.nih.gov/projects/SNP/[Sherry, S. T., et al. (2001) dbSNP:The NCBI database of genetic variation. Nucl Acids Res, 29: 308-311;Kitts, A. and Sherry, S. (2009) The single nucleotide polymorphismdatabase (dbSNP) of nucleotide sequence variation. In: The NCBI Handbook(Internet); McEntyre, J., Ostell, J., editors. Bethesda (Md.): NationalCenter for Biotechnology Information (US); 2002(www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=handbook&part=ch5)].Multiple isoforms of certain proteins may exist, e.g., as a result ofalternative RNA splicing or editing. In general, where aspects of thisdisclosure pertain to a gene or gene product, embodiments pertaining toallelic variants or isoforms are encompassed, if applicable, unlessindicated otherwise. Certain embodiments may be directed to particularsequence(s), e.g., particular allele(s) or isoform(s).

The term “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refers tothe ability of a compound to reduce, slow, halt, and/or prevent activityof a particular biological process (e.g., AR-mediated gene expression)in a cell relative to vehicle.

“Modulate” as used herein means to decrease (e.g., inhibit, reduce,suppress) or increase (e.g., stimulate, activate, enhance) a level,response, property, activity, pathway, or process. A “modulator” is anagent capable of modulating a level, response, property, activity,pathway, or process. A modulator may be an inhibitor, antagonist,activator, or agonist. In some embodiments modulation may refer to analteration, e.g., inhibition or increase, of the relevant level,response, property, activity, pathway, or process by at least about 5%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.

Anti-cancer agents encompass biotherapeutic anti-cancer agents as wellas chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agentsinclude, but are not limited to, interferons, cytokines (e.g., tumornecrosis factor, interferon α, interferon γ), vaccines, hematopoieticgrowth factors, monoclonal serotherapy, immunostimulants and/orimmunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growthfactors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN (trastuzumab),T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX(panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)).

Exemplary chemotherapeutic agents include, but are not limited to,anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRHagonists (e.g. goscrclin and leuprolide), antiandrogens (e.g. flutamideand bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA),phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A(2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalentsuch as nanoparticle albumin-bound paclitaxel (ABRAXANE),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMPdehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin,and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea anddeferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine,doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosineanalogs (e.g. cytarabine (ara C), cytosine arabinoside, andfludarabine), purine analogs (e.g. mercaptopurine and Thioguanine),Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylationinhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca²⁺ ATPase inhibitors (e.g. thapsigargin),imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g.,axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib(NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumabozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765,AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF(2)341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTORinhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus(RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI(2)7 (OSI)),oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine.

The terms “agent” and “therapeutic agent” are used herein to refer toany substance, compound (e.g., molecule), supramolecular complex,material, or combination or mixture thereof. A compound may be any agentthat can be represented by a chemical formula, chemical structure, orsequence. Example of agents, include, e.g., small molecules,polypeptides, nucleic acids (e.g., RNAi agents, antisenseoligonucleotide, aptamers), lipids, polysaccharides, etc. In general,agents may be obtained using any suitable method known in the art. Theordinary skilled artisan will select an appropriate method based, e.g.,on the nature of the agent. An agent may be at least partly purified. Insome embodiments an agent may be provided as part of a composition,which may contain, e.g., a counter-ion, aqueous or non-aqueous diluentor carrier, buffer, preservative, or other ingredient, in addition tothe agent, in various embodiments. In some embodiments an agent may beprovided as a salt, ester, hydrate, or solvate. In some embodiments anagent is cell-permeable, e.g., within the range of typical agents thatare taken up by cells and acts intracellularly, e.g., within mammaliancells, to produce a biological effect.

Certain compounds may exist in particular geometric or stereoisomericforms. Such compounds, including cis- and trans-isomers, E- andZ-isomers, R- and S-enantiomers, diastereomers, (D)-isomers,(L)-isomers, (−)- and (+)-isomers, racemic mixtures thereof, and othermixtures thereof are encompassed by this disclosure in variousembodiments unless otherwise indicated. Certain compounds may exist in avariety or protonation states, may have a variety of configurations, mayexist as solvates [e.g., with water (i.e. hydrates) or common solvents]and/or may have different crystalline forms (e.g., polymorphs) ordifferent tautomeric forms. Embodiments exhibiting such alternativeprotonation states, configurations, solvates, and forms are encompassedby the present disclosure where applicable.

The terms “assess,” “determine,” “evaluate,” and “assay” are usedinterchangeably herein to refer to any form of detection or measurement,and include determining whether a substance, signal, disease, condition,etc., is present or not. The result of an assessment may be expressed inqualitative and/or quantitative terms. Assessing may be relative orabsolute. “Assessing the presence of” includes determining the amount ofsomething that is present or determining whether it is present orabsent.

A nucleotide or amino acid residue in a first nucleic acid or protein“corresponds to” a residue in a second nucleic acid or protein if thetwo residues perform one or more corresponding functions and/or arelocated at corresponding positions in the first and second nucleic acidsor proteins. Corresponding functions are typically the same, equivalent,or substantially equivalent functions, taking into account differencesin the environments of the two nucleic acids or proteins as appropriate.Residues at corresponding positions typically align with each other whenthe sequences of the two nucleic acids or proteins are aligned tomaximize identity (allowing the introduction of gaps) using a sequencealignment algorithm or computer program such as those referred to below(see “Identity”) and/or are located at positions such that when the3-dimensional structures of the proteins is superimposed the residuesoverlap or occupy structurally equivalent positions and/or form thesame, equivalent, or substantially equivalent intramolecular and/orintermolecular contacts or bonds (e.g., hydrogen bonds). The structuresmay be experimentally determined (e.g., by X-ray crystallography or NMR)or predicted (e.g., using structure prediction or molecular modelingsoftware). An alignment may be over the entire length of one or more ofthe aligned nucleic acid or polypeptide sequences or over at least oneprotein domain (or nucleotide sequence encoding a protein domain). A“domain” of a protein is a distinct functional and/or structural unit ofa protein, e.g., an independently folding unit of a polypeptide chain.In some embodiments a domain is a portion of a protein sequenceidentified as a domain in the Conserved Domain Database of the NCBI(Marchler-Bauer, A., et al. (2013) CDD: conserved domains and proteinthree-dimensional structure. Nucleic Acids Res, 41: D384-52). In someembodiments corresponding amino acids are the same in two sequences(e.g., a lysine residue, a threonine residue) or would be consideredconservative substitutions for each other. Examples of correspondingresidues include (i) the catalytic residues of two homologous enzymesand (ii) sites for post-translational modification of a particular type(e.g., phosphorylation) within corresponding structural or functionaldomains that have similar effects on the structure or function ofhomologous proteins.

“Identity” or “percent identity” is a measure of the extent to which thesequence of two or more nucleic acids or polypeptides is the same. Thepercent identity between a sequence of interest A and a second sequenceB may be computed by aligning the sequences, allowing the introductionof gaps to maximize identity, determining the number of residues(nucleotides or amino acids) that are opposite an identical residue,dividing by the minimum of TG_(A) and TG_(B)(here TG_(A) and TG_(B) arethe sum of the number of residues and internal gap positions insequences A and B in the alignment), and multiplying by 100. Whencomputing the number of identical residues needed to achieve aparticular percent identity, fractions are to be rounded to the nearestwhole number. Sequences can be aligned with the use of a variety ofcomputer programs known in the art. For example, computer programs suchas BLAST2, BLASTN, BLASTP, Gapped BLAST, etc., may be used to generatealignments and/or to obtain a percent identity. The algorithm of Karlinand Altschul (Karlin and Altschul, Proc Natl Acad Sci USA, 87:22264-2268, 1990) modified as in Karlin and Altschul, Proc Natl Acad SciUSA, 90: 5873-5877, 1993 is incorporated into the NBLAST and XBLASTprograms of Altschul et al. [Altschul, et al. (1990) J Mol Biol, 215:403-410]. In some embodiments, to obtain gapped alignments forcomparison purposes, Gapped BLAST is utilized as described in Altschulet al. [Altschul, et al. (1997) Nucleic Acids Res, 25: 3389-3402]. Whenutilizing BLAST and Gapped BLAST programs, the default parameters of therespective programs may be used. See the Web site having URLwww.ncbi.nlm.nih.gov and/or McGinnis, S. and Madden, T L, W20-W25Nucleic Acids Research, 2004, Vol. 32, Web server issue. Other suitableprograms include CLUSTALW [Thompson, J. D., Higgins, D. G., and Gibson,T. J. (1994) Nuc Acid Res, 22: 4673-4680], CLUSTAL Omega [Sievers, F.,Wilm, A., Dineen, D., et al. (2011) Fast, scalable gernation ofhigh-qulaity protein multiple sequence alignments using Clustal Omega.Mol Sys Biol, 7: doi:10.1038/msb.2011.75], and GAP (GCG Version 9.1;which implements the Needleman & Wunsch, 1970 algorithm [Needleman, S.B. and Wunsch, C. D. (1970) J Mol Biol, 48: 443-453]). Percent identitymay be evaluated over a window of evaluation. In some embodiments awindow of evaluation may have a length of at least 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,96%, 97%, 98%, 99%, or more, e.g., 100%, of the length of the shortestof the sequences being compared. In some embodiments a window ofevaluation is at least 100; 200; 300; 400; 500; 600; 700; 800; 900;1,000; 1,200; 1,500; 2,000; 2,500; 3,000; 3,500; 4,000; 4,500; or 5,000amino acids. In some embodiments no more than 20%, 10%, 5%, or 1% ofpositions in either sequence or in both sequences over a window ofevaluation are occupied by a gap. In some embodiments no more than 20%,10%, 5%, or 1% of positions in either sequence or in both sequences areoccupied by a gap.

“Detection reagent” refers to an agent that is useful to specificallydetect a gene product, protein, or other analyte of interest, e.g., anagent that specifically binds to the gene product, protein, or otheranalyte. Examples of agents useful as detection reagents include, e.g.,nucleic acid probes or primers that hybridize to RNA or DNA to bedetected, antibodies, aptamers, or small molecule ligands that bind topolypeptides to be detected, and the like. In some embodiments adetection reagent comprises a label. In some embodiments a detectionreagent is attached to a support. Such attachment may be covalent ornoncovalent in various embodiments. Methods suitable for attachingdetection reagents or analytes to supports will be apparent to those ofordinary skill in the art. A support may be a substantially planar orflat support or may be a particulate support, e.g., an approximatelyspherical support such as a microparticle (also referred to as a “bead”,“microsphere”), nanoparticle (or like terms), or population ofmicroparticles. In some embodiments a support is a slide, chip, orfilter. In some embodiments a support is at least a portion of an innersurface of a well or other vessel, channel, flow cell, or the like. Asupport may be rigid, flexible, solid, or semi-solid (e.g., gel). Asupport may be comprised of a variety of materials such as, for example,glass, quartz, plastic, metal, silicon, agarose, nylon, or paper. Asupport may be at least in part coated, e.g., with a polymer orsubstance comprising a reactive functional group suitable for attachinga detection reagent or analyte thereto. The term “detecting” encompassesany method that involves a detecting agent and any gene product,protein, or other analyte of interest.

An “effective amount” or “effective dose” of an agent (or compositioncontaining such agent) refers to the amount sufficient to achieve adesired biological and/or pharmacological effect, e.g., when deliveredto a cell or organism according to a selected administration form,route, and/or schedule. The phrases “effective amount” and“therapeutically effective amount” are used interchangeabley. As will beappreciated by those of ordinary skill in this art, the absolute amountof a particular agent or composition that is effective may varydepending on such factors as the desired biological or pharmacologicalendpoint, the agent to be delivered, the target tissue, etc. Those ofordinary skill in the art will further understand that an “effectiveamount” may be contacted with cells or administered to a subject in asingle dose, or through use of multiple doses, in various embodiments.

The term “expression” encompasses the processes by which nucleic acids(e.g., DNA) are transcribed to produce RNA, and (where applicable) RNAtranscripts are processed and translated into polypeptides.

The terms “protein,” “peptide,” and “polypeptide” are usedinterchangeably herein and refer to a polymer of amino acid residueslinked together by peptide (amide) bonds. The terms refer to a protein,peptide, or polypeptide of any size, structure, or function. Typically,a protein, peptide, or polypeptide will be at least three amino acidslong. A protein, peptide, or polypeptide may refer to an individualprotein or a collection of proteins. One or more of the amino acids in aprotein, peptide, or polypeptide may be modified, for example, by theaddition of a chemical entity such as a carbohydrate group, a hydroxylgroup, a phosphate group, a farnesyl group, an isofarnesyl group, afatty acid group, a linker for conjugation, functionalization, or othermodification, etc. A protein, peptide, or polypeptide may also be asingle molecule or may be a multi-molecular complex. A protein, peptide,or polypeptide may be just a fragment of a naturally occurring proteinor peptide. A protein, peptide, or polypeptide may be naturallyoccurring, recombinant, or synthetic, or any combination thereof. Aprotein may comprise different domains, for example, a nucleic acidbinding domain (e.g., the gRNA binding domain of Cas9 that directs thebinding of the protein to a target site) and a nucleic acid cleavagedomain. In some embodiments, a protein comprises a proteinaceous part,e.g., an amino acid sequence constituting a nucleic acid binding domain,and an organic compound, e.g., a compound that can act as a nucleic acidcleavage agent. In some embodiments, a protein is in a complex with, oris in association with, a nucleic acid, e.g., RNA. In some embodiments,a protein comprises a ligand binding domain. In some embodiments, aprotein comprises an active site (e.g., site of biological or enzymaticactivity). In some embodiments, a protein comprises an allosteric site(e.g., site of a protein that can bind to a ligand that can be remotefrom an active site). Any of the proteins provided herein may beproduced by any method known in the art. For example, the proteinsprovided herein may be produced via recombinant protein expression andpurification, which is especially suited for fusion proteins comprisinga peptide linker. Methods for recombinant protein expression andpurification are well known, and include those described by Green andSambrook, Molecular Cloning. A Laboratory Manual [4^(th) ed., ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012)], theentire contents of which are incorporated herein by reference.

As used herein, the term “purified” refers to agents that have beenseparated from most of the components with which they are associated innature or when originally generated or with which they were associatedprior to purification. In general, such purification involves action ofthe hand of man. Purified agents may be partially purified,substantially purified, or pure. Such agents may be, for example, atleast 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, ormore than 99% pure. In some embodiments, a nucleic acid, polypeptide, orsmall molecule is purified such that it constitutes at least 75%, 80%,85%, 90%, 95%, 96%, 97%, 98%, 99%, or more, of the total nucleic acid,polypeptide, or small molecule material, respectively, present in apreparation. In some embodiments, an organic substance, e.g., a nucleicacid, polypeptide, or small molecule, is purified such that itconstitutes at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, ormore, of the total organic material present in a preparation. Purity maybe based on, e.g., dry weight, size of peaks on a chromatography tracing(GC, HPLC, etc.), molecular abundance, electrophoretic methods,intensity of bands on a gel, spectroscopic data (e.g., NMR), elementalanalysis, high throughput sequencing, mass spectrometry, or anyart-accepted quantification method. In some embodiments, water, buffersubstances, ions, and/or small molecules (e.g., synthetic precursorssuch as nucleotides or amino acids), can optionally be present in apurified preparation. A purified agent may be prepared by separating itfrom other substances (e.g., other cellular materials), or by producingit in such a manner to achieve a desired degree of purity. In someembodiments “partially purified” with respect to a molecule produced bya cell means that a molecule produced by a cell is no longer presentwithin the cell, e.g., the cell has been lysed and, optionally, at leastsome of the cellular material (e.g., cell wall, cell membrane(s), cellorganelle(s)) has been removed and/or the molecule has been separated orsegregated from at least some molecules of the same type (protein, RNA,DNA, etc.) that were present in the lysate.

The term “sample” may be used to generally refer to an amount or portionof something. A sample may be a smaller quantity taken from a largeramount or entity; however, a complete specimen may also be referred toas a sample where appropriate. A sample is often intended to be similarto and representative of a larger amount of the entity of which it is asample. In some embodiments a sample is a quantity of a substance thatis or has been or is to be provided for assessment (e.g., testing,analysis, measurement) or use. A sample may be any biological specimen.In some embodiments, a sample is a cell lysate (e.g., a fluid comprisingthe contents of lysed cells). In some embodiments a sample comprises abody fluid such as blood, cerebrospinal fluid, (CSF), sputum, lymph,mucus, saliva, a glandular secretion, or urine. In some embodiments asample comprises cells, tissue, or cellular material (e.g., materialderived from cells, such as a cell lysate or fraction thereof). A samplemay be obtained from (i.e., originates from, was initially removed from)a subject. Methods of obtaining biological samples from subjects areknown in the art and include, e.g., tissue biopsy, such as excisionalbiopsy, incisional biopsy, core biopsy; fine needle aspiration biopsy;surgical excision, brushings; lavage; or collecting body fluids that maycontain cells, such as blood, sputum, lymph, mucus, saliva, or urine. Asample is often intended to be similar to and representative of a largeramount of the entity of which it is a sample. A sample of a cell linecomprises a limited number of cells of that cell line. In someembodiments a sample may be obtained from an individual who has beendiagnosed with or is suspected of having a neurodegenerative disease. Insome embodiments a sample is obtained from skin or blood. In someembodiments a sample contains at least some intact cells. In someembodiments a sample retains at least some of the microarchitecture of atissue from which it was removed. A sample may be subjected to one ormore processing steps, e.g., after having been obtained from a subject,and/or may be split into one or more portions. The term sampleencompasses processed samples, portions of samples, etc., and suchsamples are, where applicable, considered to have been obtained from thesubject from whom the initial sample was removed. A sample may beprocured directly from a subject, or indirectly, e.g., by receiving thesample from one or more persons who procured the sample directly fromthe subject, e.g., by performing a biopsy, surgery, or other procedureon the subject. In some embodiments a sample may be assigned anidentifier (ID), which may be used to identify the sample as it istransported, processed, analyzed, and/or stored. In some embodiments thesample ID corresponds to the subject from whom the sample originated andallows the sample and/or results obtained by assessing the sample to bematched with the subject.

In some embodiments the sample has an identifier affixed thereto.

The term “compound” as used herein encompasses any small molecule,peptide, nucleic acid, protein, or derivative thereof that may be usedto modulate a target of interest (e.g., a transcription factor). Incertain embodiments, a compound identified in the present disclosure isable to modulate the androgen receptor. The term “compound” and “agent”are used interchangeably.

A “subject” may be any vertebrate organism in various embodiments. Asubject may be individual to whom an agent is administered, e.g., forexperimental, diagnostic, and/or therapeutic purposes or from whom asample is obtained or on whom a procedure is performed. In someembodiments a subject is a mammal, e.g. a human, non-human primate, orrodent (e.g., mouse, rat, rabbit). In some embodiments, a subject hasbeen diagnosed with prostate cancer.

“Treat,” “treating,” and similar terms as used herein in the context oftreating a subject refer to providing medical and/or surgical managementof a subject. Treatment may include, but is not limited to,administering an age or composition (e.g., a pharmaceutical composition)to a subject. Treatment is typically undertaken in an effort to alterthe course of a disease (which term is used to indicate any disease,disorder, syndrome or undesirable condition warranting or potentiallywarranting therapy) in a manner beneficial to the subject. The effect oftreatment may include reversing, alleviating, reducing severity of,delaying the onset of, curing, inhibiting the progression of, and/orreducing the likelihood of occurrence or recurrence of the disease orone or more symptoms or manifestations of the disease. A therapeuticagent may be administered to a subject who has a disease or is atincreased risk of developing a disease relative to a member of thegeneral population. In some embodiments a therapeutic agent may beadministered to a subject who has had a disease but no longer showsevidence of the disease. The agent may be administered e.g., to reducethe likelihood of recurrence of evident disease. A therapeutic agent maybe administered prophylactically, i.e., before development of anysymptom or manifestation of a disease. “Prophylactic treatment” refersto providing medical and/or surgical management to a subject who has notdeveloped a disease or does not show evidence of a disease in order,e.g., to reduce the likelihood that the disease will occur or to reducethe severity of the disease should it occur. The subject may have beenidentified as being at risk of developing the disease (e.g., atincreased risk relative to the general population or as having a riskfactor that increases the likelihood of developing the disease.

“Expose,” “exposing,” and similar terms as used herein in the context ofa biological receptor (e.g., an androgen receptor or variant thereof)refers to subjecting the biological receptor, or allowing the biologicalreceptor to be subjected to an action, influence, or condition, e.g.,the direct or indirect action or influence of a compound of theinvention, or a condition created or maintained directly or indirectlyby a compound of the invention.

“Contact,” “contacting,” and similar terms as used herein may refer toeither direct or indirect contact, or both.

“Bind”, “binding,” and similar terms as used herein may refer to adirect interaction between a compound and a receptor, or fragmentthereof, or an indirect interaction, for example, involving one or moreinteractome partners.

A “variant” of a particular polypeptide or polynucleotide has one ormore additions, substitutions, and/or deletions with respect to thepolypeptide or polynucleotide, which may be referred to as the “originalpolypeptide” or “original polynucleotide,” respectively. An addition maybe an insertion or may be at either terminus. A variant may be shorteror longer than the original polypeptide or polynucleotide. The term“variant” encompasses “fragments”. A “fragment” is a continuous portionof a polypeptide or polynucleotide that is shorter than the originalpolypeptide. In some embodiments a variant comprises or consists of afragment. In some embodiments a fragment or variant is at least 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more aslong as the original polypeptide or polynucleotide.

In some embodiments a variant is a biologically active variant, i.e.,the variant at least in part retains at least one activity of theoriginal polypeptide or polynucleotide. In some embodiments a variant atleast in part retains more than one or substantially all knownbiologically significant activities of the original polypeptide orpolynucleotide. An activity may be, e.g., a catalytic activity, bindingactivity, ability to perform or participate in a biological structure orprocess, etc. In some embodiments an activity of a variant may be atleast 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more, of theactivity of the original polypeptide or polynucleotide, up toapproximately 100%, approximately 125%, or approximately 150% of theactivity of the original polypeptide or polynucleotide, in variousembodiments. In some embodiments, a variant, e.g., a biologically activevariant, comprises or consists of a polypeptide at least 95%, 96%, 97%,98%, 99%, 99.5%, or 100% identical to an original polypeptide over atleast 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of theoriginal polypeptide. In some embodiments an alteration, e.g., asubstitution or deletion, e.g., in a functional variant, does not alteror delete an amino acid or nucleotide that is known or predicted to beimportant for an activity, e.g., a known or predicted catalytic residueor residue involved in binding a substrate or cofactor. Variants may betested in one or more suitable assays to assess activity.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which constitute a part of thisspecification, illustrate several exemplary embodiments of the inventionand together with the description, serve to explain certain principlesof the invention. The embodiments disclosed in the drawings areexemplary and do not limit the scope of this disclosure.

FIGS. 1A to 1B show that prostate cancer cell lines are sensitive tosmall molecules. The cell viability 48 hours after treatment with KARv1(compound (1)) (FIG. 1A) and KARv1 negative control (FIG. 1B) are shown.

FIGS. 2A to 2B show that compound (1) stagnates prostate cancer cellproliferation. The relative proliferation at 72 hours (FIG. 2A) and thepercent confluence (FIG. 2B) for different cancer cell lines with andwithout compound (1) treatment are shown.

FIGS. 3A to 3C show that compound (1) stagnates prostate cancer cellproliferation in PC3 (AR-) cell lines. The results for KARv1 treatment(FIG. 3A) and KARv1 negative control (FIG. 3B) are shown. The percentconfluence with and without compound (1) treatment at 72 hours is alsoshown (FIG. 3C).

FIGS. 4A to 4C show that compound (1) stagnates prostate cancer cellproliferation in DU-145 (AR-) cell lines. The results for KARv1treatment (FIG. 4A) and KARv1 negative control (FIG. 4B) are shown. Thepercent confluence with and without (1) treatment at 72 hours is alsoshown (FIG. 4C).

FIGS. 5A to 5C show that (1) stagnates prostate cancer cellproliferation in VCaP (AR+) cell lines. The results for KARv1 treatment(FIG. 5A) and KARv1 negative control (FIG. 5B) are shown. The percentconfluence with and without (1) treatment at 72 hours is also shown(FIG. 5C).

FIGS. 6A to 6C show that (1) stagnates prostate cancer cellproliferation in LNCaP (AR+) cell lines. The results for KARv1 treatment(FIG. 6A) and KARv1 negative control (FIG. 6B) are shown. The percentconfluence with and without (1) treatment at 72 hours is also shown(FIG. 6C).

FIGS. 7A to 7C show that (1) stagnates prostate cancer cellproliferation in 22Rv1 (AR+) cell lines. The results for KARv1 treatment(FIG. 7A) and KARv1 negative control (FIG. 7B) are shown. The percentconfluence with and without (1) treatment at 72 hours is also shown(FIG. 7C).

FIGS. 8A to 8C show that (1) does not form aggregates at IC₅₀ in RPMI(FIG. 8A), DMSO (FIG. 8B), or PBS (FIG. 8C).

FIGS. 9A to 9C show that KARv2A does not form aggregates at IC₅₀ in RPMI(FIG. 9A), DMSO (FIG. 9B), or PBS (FIG. 9C).

FIGS. 10A to 10B show that KARv compounds modulate AR-mediated geneexpression in both 22Rv1 (FIG. 10A) and VCaP-16 (FIG. 10B) cell lines.KARv2A and KARv2B represent the isolated endo or exo stereoisomers ofKARv2. FIG. 10C shows the structure of KARv3 used in FIGS. 10A and O1B.

FIGS. 11A to 11B show that KARv compounds decrease AR-v7 protein levelsin both 22Rv1 (FIG. 11A) and VCaP-16 (FIG. 11B) cell lines.

FIG. 12 shows the preliminary mechanism of action is through AR-v7 andARE perturbation.

FIG. 13 shows the EMSA mechanism of action of compound (2) (left panel)and compound (1) (right panel).

FIG. 14 shows the androgen receptor DNA binding domain. FIG. 14 isadapted from Shaffer et al. PNAS, 2004, 101; 14, 4758.

FIG. 15 shows the results of preliminary docking studies of compound (1)(left panel) with AR-DBD (right panel).

FIG. 16 shows the structure of compound (1) with AR-DBD.

FIGS. 17A to 17D show the structure of compound (1) with AR-DBD in thefront (FIG. 17A), front undercarriage (FIG. 17B), and back views (FIGS.17C and 17D).

FIG. 18 shows the results of preliminary docking studies of compound (2)with AR-DBD.

FIGS. 19A to 19D show the structure of compound (2) with AR-DBD in thefront (FIG. 19A), front undercarriage (FIG. 19B), and back views (FIGS.19C and 19D).

FIG. 20 shows the structure of compound (2) with AR-DBD.

FIG. 21 shows the androgen receptor DNA binding domain cloningprocedure.

FIGS. 22A and 22B show GST-AR-DBD relative protein quantitation. Theresults with Coomassie staining are shown in FIG. 22A and the BSA linearregression is shown in FIG. 22B.

FIG. 23 shows the ARE oligo assessment.

FIG. 24 shows new oligo and protein function.

FIG. 25 shows GST-AR-DBD/(2)-003 competition.

FIG. 26 shows the (1) proposed initial SAR and chemical optimization.

FIG. 27 shows synthetic efforts towards compound (1).

FIG. 28 shows synthetic efforts towards compound (1).

FIG. 29 shows synthetic efforts towards compound (1).

FIG. 30 shows the chemical optimization of compound (2).

FIG. 31 shows representative structural combinations.

DETAILED DESCRIPTION

Androgen receptor antagonists are a class of drugs which preventandrogens like testosterone and dihydrotestosterone (DHT) from mediatingtheir biological effects in the body. They act by blocking the androgenreceptor (AR) and/or inhibiting or suppressing androgen production. ARantagonists, also called antiandrogens, are used to treat an assortmentof androgen-dependent conditions. In males, antiandrogens are used inthe treatment of prostate cancer, benign prostatic hyperplasia,androgenic alopecia (pattern hair loss), hypersexuality, paraphilias,and precocious puberty. In women, antiandrogens are used to treat acne,seborrhea, hidradenitis suppurativa, hirsutism, and hyperandrogenism,such as that which occurs in polycystic ovary syndrome (PCOS).

Androgens such as testosterone and DHT are involved in the developmentand progression of prostate cancer. They act as growth factors in theprostate gland, stimulating cell division and tissue growth. Therapeuticmodalities that reduce androgen signaling in the prostate gland,referred to collectively as androgen deprivation therapy, are able tosignificantly slow the course of prostate cancer and extend life in menwith the disease. Currently marketed antiandrogens are effective inslowing the progression of prostate cancer, but they are not generallycurative, and with time, the disease adapts and androgen deprivationtherapy eventually becomes ineffective. The compounds described hereinare designed to overcome this problem.

Compounds of the Invention

Provided by the present disclosure are compounds of Formulae (I), (II),(IA), (IB), (IC), (ID), (IE), (IF), (IF-a), (IF-b), (IF-c), (IF-d),(IF-e), (IF-a3), (IF-b3), (IF-c3), (IF-d3), (IF-e3), (IF-a4), (IF-b4),(IF-c4), (IF-d4), (IF-e3), (IF-e4), (IIA), (IIB), (IIC), (IID), (IIA-a),(IIA-b), (IIA-c), and (IIA-d), and pharmaceutically acceptable salts,solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, and prodrugs thereof, collectivelyreferred to herein as compounds of the invention.

Compounds of the invention may bind an androgen receptor, or a variantthereof, and/or may be modulators (e.g., activators, inhibitors,agonists or antagonists) of an androgen receptor, or a variant thereof.Exemplary amino acid sequences of androgen receptors and variantsthereof are provided herein. As such, the compounds are useful inmodulating transcription and in the treatment and/or prevention of avariety of diseases and conditions, for example, proliferative diseasessuch as cancer. Also provided are related pharmaceutical compositions,methods, and uses of the compounds described herein.

In one aspect, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is an optionally substituted heterocyclyl, or optionally substitutedheteroaryl;

L and L₁, independently are absent, or are optionally substituted C₁₋₆aliphatic, or optionally substituted C₁₋₆ heteroaliphatic;

Q is hydrogen, halogen, —CN, —NO₂, —R^(a), —OH, —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)N(R^(a))₂, —NH₂, —N(R^(a))₂, —NC(O)R^(a),—NC(O)OR^(a), or —NC(O)N(R^(a))₂;

each occurrence of R^(a), independently, is optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl; R₁ is optionallysubstituted aliphatic, or optionally substituted heteroaliphatic,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; R₂ ishydrogen, optionally substituted aliphatic, or optionally substitutedheteroaliphatic; X₁ and X₂, independently, are selected from hydrogen,halogen, —OH, or optionally substituted aliphatic, or X₁ and X₂ togetherform an oxo (═O) group; and wherein Q and L, Q and L1, Q and R₂ or Q andX₁ may combine to form a ring.

In an embodiment, Q and L are substituents capable of combining to forma ring (for example, by combining radicals generated by removing one ormore hydrogen atoms from Q and L, respectively), and Q and L combine toform a ring as in Formula (IA):

or a pharmaceutically acceptable salt thereof. Non-limiting examples ofcompounds having the structure of Formula (IA) are shown in FIG. 29. Incertain embodiments, Q and L do not combine to form a ring.

In an embodiment, Q and L₁ combine to form a ring, as in Formula (IB):

or a pharmaceutically acceptable salt thereof. Non-limiting examples ofcompounds having the structure of Formula (IB) are shown in FIG. 26. Inanother embodiment, Q and L₁ do not combine to form a ring.

In an embodiment, Q and R₂ combine to form a ring, as in the compound ofFormula (IC):

or a pharmaceutically acceptable salt thereof. Non-limiting examples ofcompounds having the structure of Formula (IC) are shown in FIG. 26. Inanother embodiment, Q and R₂ do not combine to form a ring.

In another embodiment, Q and X₁ combine to form a ring, as in thecompound of Formula (ID):

or a pharmaceutically acceptable salt thereof. Non-limiting examples ofcompounds having the structure of Formula (ID) are shown in FIG. 26. Inanother embodiment, Q and X₁ do not combine to form a ring.

In an embodiment, the compound of Formula (I) is of Formula (IF):

or a pharmaceutically acceptable salt thereof, wherein:

L is absent, optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic;

each occurrence of R, independently, is halogen, —CN, —NO₂, —R^(a), —OH,—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(a))₂, —NH₂, —N(R^(a))₂,—NC(O)R^(a), —NC(O)OR^(a), or —NC(O)N(R^(a))₂;

each occurrence of R^(a), independently, is optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R₁ is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

R₂ is hydrogen, optionally substituted aliphatic, or optionallysubstituted heteroaliphatic;

Z₁ and Z₂ are independently absent, C₁₋₂ alkylene, or

provided that only one of Z₁ and Z₂ is

R₃ is optionally substituted aliphatic, optionally substitutedheteroaliphatic, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

n is 0-3.

In an embodiment, the compound of Formula (I) is notN-(2-((1S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)ethyl)-3-((1-(cyclopropanecarbonyl)piperidin-4-yl)oxy)benzamide,or a stereoisomer thereof. In a particular embodiment, the compound ofFormula (I) is not compound (1).

Several embodiments of Formula (IF) are provided, including Formulae(IF-a), (IF-b), (IF-c), (IF-d), and (IF-e), and further includingFormulae (IF-a3), (IF-a4), (IF-b3), (IF-b4), (IF-c3), (IF-c4), (IF-d3),(IF-d4), (IF-e3), and (IF-e4), as defined herein. In a particularembodiment, the compound of Formula (IF) has the structure of Formula(IF-a) or Formula (IF-b). In a more particular embodiment, the compoundof Formula (IF) has a structure selected from Formulae (IF-a3), (IF-a4),(IF-b3), and (IF-b4).

In an embodiment, L is absent. In an embodiment, L is C₁₋₆ alkylene, forexample, methylene, ethylene, or propylene.

In an embodiment R₁ is optionally substituted C₅₋₁₀ cycloaliphatic. Inan embodiment R₁ is optionally substituted C₆₋₁₀ aryl. In an embodimentR₁ is optionally substituted C₆₋₁₀ heteroaryl. In a particularembodiment, R₁ is C₅₋₇ monocyclic carbocyclyl. In a particularembodiment, R₁ is C₅₋₇ monocyclic heterocyclyl. In a particularembodiment, R₁ is C₅₋₁₀ fused bicyclic carbocyclyl. In a particularembodiment, R₁ is C₅₋₁₀ fused bicyclic heterocyclyl. In a particularembodiment, R₁ is C₅₋₁₀ bridged bicyclic carbocyclyl. In a particularembodiment, R₁ is C₅₋₁₀ bridged bicyclic heterocyclyl. In a particularembodiment, R₁ is C₅₋₁₀ bridged tricyclic carbocyclyl. In a particularembodiment, R₁ is C₅₋₁₀ bridged tricyclic heterocyclyl.

In an embodiment R₁ is selected from the following:

In a particular embodiment, R₁ is selected from:

In a particular embodiment, R₁ is selected from:

In a particular embodiment, R₁ is selected from:

In a particular embodiment, R₁ is selected from:

In a particular embodiment, R₁ is selected from:

In a particular embodiment, R₁ is selected from:

In an embodiment, R₂ is hydrogen. In an embodiment, R₂ is optionallysubstituted C₁₋₆ alkyl, e.g., C₁₋₆ haloalkyl.

In an embodiment, R₃ is optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₃₋₆ cycloalkyl,optionally substituted C₃₋₆ heterocycloalkyl, optionally substitutedC₆₋₁₀ aryl, or optionally substituted C₂₋₁₀ heteroaryl.

In an embodiment, R₃ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₆cycloalkyl, optionally substituted benzyl, optionally substitutedphenyl, or optionally substituted pyridyl (for example, 2-pyridyl,3-pyridyl, or 4-pyridyl).

In an embodiment, R₃ is selected from:

In a particular embodiment, R₃ is selected from:

In a particular embodiment, R₃ is selected from:

In a particular embodiment, R₃ is selected from:

In an embodiment, n is 0, 1, 2, or 3. In a particular embodiment, n is1, 2, or 3. In a particular embodiment, n is 0. In a particularembodiment, n is 1.

Also provided are the following particular embodiments:

In Formula (IF-a3): R₁ is optionally substituted C₅₋₁₀ bridged bicycliccarbocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ is optionallysubstituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substitutedC₁₋₆ alkyl; and n is 0.

In Formula (IF-a3): R₁ is optionally substituted C₅₋₁₀ fused bicyclicheterocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ isoptionally substituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionallysubstituted C₁₋₆ alkyl; and n is 0.

In Formula (IF-a3): R₁ is optionally substituted C₅₋₁₀ bridged tricycliccarbocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ is optionallysubstituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substitutedC₁₋₆ alkyl; and n is 0.

In Formula (IF-a3): R₁ is optionally substituted C₅₋₇ monocycliccarbocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ is optionallysubstituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substitutedC₁₋₆ alkyl; and n is 0.

In Formula (IF-a3): R₁ is optionally substituted C₆₋₁₀ heteroaryl; L isoptionally substituted C₁₋₆ alkylene; R₂ is optionally substituted C₁₋₆alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substituted C₁₋₆ alkyl; andn is 0.

In Formula (IF-a3): R₁ is optionally substituted C₆₋₁₀ aryl; L isoptionally substituted C₁₋₆ alkylene; R₂ is optionally substituted C₁₋₆alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substituted C₁₋₆ alkyl; andn is 0.

In Formula (IF-a4): R₁ is optionally substituted C₅₋₁₀ bridged bicycliccarbocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ is optionallysubstituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substitutedC₁₋₆ alkyl; and n is 0.

In Formula (IF-a4): R₁ is optionally substituted C₅₋₁₀ fused bicyclicheterocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ isoptionally substituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionallysubstituted C₁₋₆ alkyl; and n is 0.

In Formula (IF-a4): R₁ is optionally substituted C₅₋₁₀ bridged tricycliccarbocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ is optionallysubstituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substitutedC₁₋₆ alkyl; and n is 0.

In Formula (IF-a4): R₁ is optionally substituted C₅₋₇ monocycliccarbocyclyl; L is optionally substituted C₁₋₆ alkylene; R₂ is optionallysubstituted C₁₋₆ alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substitutedC₁₋₆ alkyl; and n is 0.

In Formula (IF-a4): R₁ is optionally substituted C₆₋₁₀ heteroaryl; L isoptionally substituted C₁₋₆ alkylene; R₂ is optionally substituted C₁₋₆alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substituted C₁₋₆ alkyl; andn is 0.

In Formula (IF-a4): R₁ is optionally substituted C₆₋₁₀ aryl; L isoptionally substituted C₁₋₆ alkylene; R₂ is optionally substituted C₁₋₆alkyl; R₃ is C₃₋₆ cycloalkyl, or optionally substituted C₁₋₆ alkyl; andn is 0.

In certain embodiments, the compound of Formula (I) is selected from thecompounds of Table 1, and pharmaceutically acceptable salts thereof.

TABLE 1 Compounds of Formula (I). Compound Number Structure I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

  (mixture of stereoisomers) I-38

  (mixture of stereoisomers) I-39

  (mixture of stereoisomers) I-40

  (mixture of stereoisomers)

In another aspect, provided herein is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

L₁ is absent, or is optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic;

L₂ is absent, or is optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₁₋₆ heteroaliphatic; X is —O—, —S— or —N(R)—;

R is hydrogen, or optionally substituted alkyl;

Q₁, Q₂, and Q₃, independently, are ═N— or ═C(R₁)—;

R₁ is hydrogen, halogen, —CN, —NO₂, —R^(a), —OH, —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)N(R^(a))₂, —NH₂, —N(R^(a))₂, —NC(O)R^(a),—NC(O)OR^(a), or —NC(O)N(R^(a))₂;

each occurrence of R^(a), independently, is optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R₂ is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

R₃ is optionally substituted alkyl or optionally substituted cycloalkyl;

R₄ is hydrogen or optionally substituted alkyl; and

R₅ is optionally substituted aryl or optionally substituted heteroaryl.

In an embodiment Q₁ and Q₃ are and Q₂ is ═C(R₁)—, and the compound ofFormula (II) has the structure of Formula (IIA):

or a pharmaceutically acceptable salt thereof.

In an embodiment X is —N(R)—, Q₁ and Q₃ are and Q₂ is ═C(H)—, and thecompound of Formula (II) has the structure of Formula (IIB):

or a pharmaceutically acceptable salt thereof.

In an embodiment Q₁ and Q₃ are ═C(H)—, Q₂ is ═N—, and the compound ofFormula (II) has the structure of Formula (IIC):

or a pharmaceutically acceptable salt thereof.

In an embodiment Q₁, Q₂, and Q₃ are ═C(H)—, and the compound of Formula(II) has the structure of Formula (IID):

or a pharmaceutically acceptable salt thereof.

Several embodiments of Formulae (IIA)-(IID) are provided. If present, R₁is hydrogen, optionally substituted aliphatic, optionally substitutedamino, optionally substituted aryl, optionally substituted heterocyclyl,or optionally substituted heteroaryl. In a particular embodiment, R₁ ishydrogen. In a particular embodiment, R₁ is optionally substituted C₁₋₆alkyl (e.g., methyl, ispoproyl, trifluoromethyl, acetyl, and the like).In a particular embodiment, R₁ is optionally substituted amino (e.g.,methylamino, benzylamino, dimethylamino, and the like). In a particularembodiment, R₁ is optionally substituted phenyl (e.g., toluyl,4-chlorophenyl, and the like). In a particular embodiment, R₁ isoptionally substituted heterocyclyl (e.g., pyrollidinyl, piperidinyl,and the like). In a particular embodiment, R₁ is optionally substitutedheteroaryl (e.g., imidazoyl, thien-2-yl, pyridyl, and the like).

In an embodiment, R₂ is optionally substituted C₅₋₁₀ cycloaliphatic,optionally substituted C₆₋₁₀ aryl or optionally substituted C₆₋₁₀heteroaryl. In a particular embodiment, R₂ is C₅₋₇ monocycliccarbocyclyl. In a particular embodiment, R₂ is C₅₋₇ monocyclicheterocyclyl. In a particular embodiment, R₂ is C₅₋₁₀ fused bicycliccarbocyclyl. In a particular embodiment, R₂ is C₅₋₁₀ fused bicyclicheterocyclyl. In a particular embodiment, R₂ is C₅₋₁₀ bridged bicycliccarbocyclyl. In a particular embodiment, R₂ is C₅₋₁₀ bridged bicyclicheterocyclyl. In a particular embodiment, R₂ is C₅₋₁₀ bridged tricycliccarbocyclyl. In a particular embodiment, R₂ is C₅₋₁₀ bridged tricyclicheterocyclyl.

In an embodiment R₂ is selected from the following:

In a particular embodiment, R₂ is selected from:

In a particular embodiment, R₂ is selected from:

In a particular embodiment, R₂ is selected from:

In a particular embodiment, R₂ is selected from:

In a particular embodiment, R₂ is selected from:

In a particular embodiment, R₂ is selected from:

In an embodiment, L₁ is absent. In an embodiment, L₁ is C₁₋₆ alkylene,for example, methylene, ethylene, or propylene.

If present, in certain embodiments, X is —N(H)—, X is —N(R)—, X is —S—,or X is —O—.

In an embodiment, R₃ is optionally substituted alkyl. In an embodiment,R₃ is optionally substituted cycloalkyl. In a particular embodiment, R₃is C₁₋₆ alkyl (e.g., methyl). In a particular embodiment, R₃ is C₁₋₆haloalkyl (e.g., trifluoromethyl). In a particular embodiment, R₃ isC₃₋₆ cycloalkyl (e.g., cyclopropyl).

In an embodiment, R₄ is C₁₋₆ alkyl. In a particular embodiment, R₄ ismethyl.

In an embodiment, R₅ is an optionally substituted monocyclic aryl (e.g.,tolyl, chlorophenyl, and the like). In an embodiment, R₅ is anoptionally substituted bicyclic aryl (e.g., naphthyl and the like). Inan embodiment, R₅ is an optionally substituted monocyclic heteroaryl(e.g., pyridyl, pyrimidinyl, thienyl, and the like). In an embodiment,R₅ is an optionally substituted bicyclic heteroaryl (e.g., quinolinyl,indolyl, and the like).

In an embodiment, R₅ is selected from the following:

In certain embodiments, the compound of Formula (II) has a structureselected from the following:

and pharmaceutically acceptable salts thereof.

Also provided are the following particular embodiments:

In Formula (IIA): X is —S—; L₁ is optionally substituted C₁₋₆ alkylene;L₂ is optionally substituted C₁₋₆ alkylene; R₁ is hydrogen; R₂ isoptionally substituted C₅₋₁₀ bridged bicyclic carbocyclyl; R₃ isoptionally substituted C₁₋₆ alkyl; R₄ is optionally substituted C₁₋₆alkyl; and R₅ is optionally substituted aryl, or optionally substitutedheteroaryl.

In Formula (IIA): X is —S—; L₁ is optionally substituted C₁₋₆ alkylene;L₂ is optionally substituted C₁₋₆ alkylene; R₁ is hydrogen; R₂ isoptionally substituted C₅₋₁₀ fused bicyclic heterocyclyl; R₃ isoptionally substituted C₁₋₆ alkyl; R₄ is optionally substituted C₁₋₆alkyl; and R₅ is optionally substituted aryl, or optionally substitutedheteroaryl.

In Formula (IIA): X is —S—; L₁ is optionally substituted C₁₋₆ alkylene;L₂ is optionally substituted C₁₋₆ alkylene; R₁ is hydrogen; R₂ isoptionally substituted C₅₋₁₀ bridged tricyclic carbocyclyl; R₃ isoptionally substituted C₁₋₆ alkyl; R₄ is optionally substituted C₁₋₆alkyl; and R₅ is optionally substituted aryl, or optionally substitutedheteroaryl.

In Formula (IIA): X is —S—; L₁ is optionally substituted C₁₋₆ alkylene;L₂ is optionally substituted C₁₋₆ alkylene; R₁ is hydrogen; R₂ isoptionally substituted C₅₋₁₀ monocyclic carbocyclyl; R₃ is optionallysubstituted C₁₋₆ alkyl; R₄ is optionally substituted C₁₋₆ alkyl; and R₅is optionally substituted aryl, or optionally substituted heteroaryl.

In Formula (IIA): X is —S—; L₁ is optionally substituted C₁₋₆ alkylene;L₂ is optionally substituted C₁₋₆ alkylene; R₁ is hydrogen; R₂ isoptionally substituted C₆₋₁₀ heteroaryl; R₃ is optionally substitutedC₁₋₆ alkyl; R₄ is optionally substituted C₁₋₆ alkyl; and R₅ isoptionally substituted aryl, or optionally substituted heteroaryl.

In Formula (IIA): X is —S—; L₁ is optionally substituted C₁₋₆ alkylene;L₂ is optionally substituted C₁₋₆ alkylene; R₁ is hydrogen; R₂ isoptionally substituted C₆₋₁₀ aryl; R₃ is optionally substituted C₁₋₆alkyl; R₄ is optionally substituted C₁₋₆ alkyl; and R₅ is optionallysubstituted aryl, or optionally substituted heteroaryl.

In certain embodiments, the compound of Formula (II) is selected fromthe compounds of Table 2 and pharmaceutically acceptable salts thereof.

TABLE 2 Compounds of Formula (II). Compound Number Structure II-3

  (mixture of stereoisomers) II-4

  (mixture of stereoisomers) II-5

  (mixture of stereoisomers) II-6

  (mixture of stereoisomers) II-7

  (mixture of stereoisomers)Pharmaceutical Compositions, Kits, and Administration

The present disclosure provides pharmaceutical compositions comprising acompound as described herein, and optionally a pharmaceuticallyacceptable excipient. In one aspect, provided herein is a pharmaceuticalcomposition comprising a composition of the invention and apharmaceutically acceptable excipient.

In certain embodiments, the compound described herein is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount. In certain embodiments, the effective amount is anamount effective for treating a proliferative disease (e.g., cancer,particularly prostate cancer, more particularly castration resistantprostate cancer) in a subject in need thereof. In certain embodiments,the effective amount is an amount effective for preventing aproliferative disease (e.g., cancer, particularly prostate cancer, moreparticularly castration resistant prostate cancer) in a subject in needthereof. In certain embodiments, the effective amount is an amounteffective for reducing the risk of developing a disease (e.g., aproliferative disease such as castration resistant prostate cancer) in asubject in need thereof. In certain embodiments, the effective amount isan amount effective for inhibiting or antagonizing the activity (e.g.,aberrant activity, such as increased activity) of a biological receptor(e.g., an androgen receptor or a variant thereof) in a subject or cell.

In certain embodiments, the subject is an animal. The animal may be ofeither sex and may be at any stage of development. In certainembodiments, the subject described herein is a human. In certainembodiments, the subject is a non-human animal. In certain embodiments,the subject is a mammal. In certain embodiments, the subject is anon-human mammal. In certain embodiments, the subject is a domesticatedanimal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a companion animal, such as a dog or cat. Incertain embodiments, the subject is a livestock animal, such as a cow,pig, horse, sheep, or goat. In certain embodiments, the subject is a zooanimal. In another embodiment, the subject is a research animal, such asa rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certainembodiments, the animal is a genetically engineered animal. In certainembodiments, the animal is a transgenic animal (e.g., transgenic miceand transgenic pigs).

In certain embodiments, the cell is present in vitro. In certainembodiments, the cell is present in vivo.

In certain embodiments, the effective amount is an amount effective forinhibiting the activity of a protein kinase by at least about 10%, atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, at least about 95%, or at least about 98%.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include bringing the compound described herein (i.e., the“active ingredient”) into association with a carrier or excipient,and/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping, and/or packaging the product into a desiredsingle- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1-1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier or excipient. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are alsocontemplated as being within the scope of this disclosure.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration). In certain embodiments, the compoundor pharmaceutical composition described herein is suitable for topicaladministration to the eye of a subject.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. An effective amount may be included in a single dose(e.g., single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to asubject or applied to a tissue or cell, any two doses of the multipledoses include different or substantially the same amounts of a compounddescribed herein. In certain embodiments, when multiple doses areadministered to a subject or applied to a tissue or cell, the frequencyof administering the multiple doses to the subject or applying themultiple doses to the tissue or cell is three doses a day, two doses aday, one dose a day, one dose every other day, one dose every third day,one dose every week, one dose every two weeks, one dose every threeweeks, or one dose every four weeks. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the tissue or cell is one dose per day. In certainembodiments, the frequency of administering the multiple doses to thesubject or applying the multiple doses to the tissue or cell is twodoses per day. In certain embodiments, the frequency of administeringthe multiple doses to the subject or applying the multiple doses to thetissue or cell is three doses per day. In certain embodiments, whenmultiple doses are administered to a subject or applied to a tissue orcell, the duration between the first dose and last dose of the multipledoses is one day, two days, four days, one week, two weeks, three weeks,one month, two months, three months, four months, six months, ninemonths, one year, two years, three years, four years, five years, sevenyears, ten years, fifteen years, twenty years, or the lifetime of thesubject, tissue, or cell. In certain embodiments, the duration betweenthe first dose and last dose of the multiple doses is three months, sixmonths, or one year. In certain embodiments, the duration between thefirst dose and last dose of the multiple doses is the lifetime of thesubject, tissue, or cell. In certain embodiments, a dose (e.g., a singledose, or any dose of multiple doses) described herein includesindependently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg,between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, orbetween 1 g and 10 g, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 1 mg and 3 mg, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 3 mg and 10 mg, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 10 mg and 30 mg, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 30 mg and 100 mg, inclusive, of a compound described herein.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult. In certain embodiments, adose described herein is a dose to an adult human whose body weight is70 kg.

A compound or composition, as described herein, can be administered incombination with one or more additional pharmaceutical agents (e.g.,therapeutically and/or prophylactically active agents). The compounds orcompositions can be administered in combination with additionalpharmaceutical agents that improve their activity (e.g., activity (e.g.,potency and/or efficacy) in treating a disease in a subject in needthereof, in preventing a disease in a subject in need thereof, inreducing the risk to develop a disease in a subject in need thereof,and/or in inhibiting the activity of a protein kinase in a subject orcell), improve bioavailability, improve safety, reduce drug resistance,reduce and/or modify metabolism, inhibit excretion, and/or modifydistribution in a subject or cell. It will also be appreciated that thetherapy employed may achieve a desired effect for the same disorder,and/or it may achieve different effects. In certain embodiments, apharmaceutical composition described herein including a compounddescribed herein and an additional pharmaceutical agent shows asynergistic effect that is absent in a pharmaceutical compositionincluding one of the compound and the additional pharmaceutical agent,but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichare different from the compound or composition and may be useful as,e.g., combination therapies. Pharmaceutical agents includetherapeutically active agents. Pharmaceutical agents also includeprophylactically active agents. Pharmaceutical agents include smallorganic molecules such as drug compounds (e.g., compounds approved forhuman or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful for treating and/or preventing a disease(e.g., proliferative disease, hematological disease, neurologicaldisease, painful condition, psychiatric disorder, or metabolicdisorder). Each additional pharmaceutical agent may be administered at adose and/or on a time schedule determined for that pharmaceutical agent.The additional pharmaceutical agents may also be administered togetherwith each other and/or with the compound or composition described hereinin a single dose or administered separately in different doses. Theparticular combination to employ in a regimen will take into accountcompatibility of the compound described herein with the additionalpharmaceutical agent(s) and/or the desired therapeutic and/orprophylactic effect to be achieved. In general, it is expected that theadditional pharmaceutical agent(s) in combination be utilized at levelsthat do not exceed the levels at which they are utilized individually.In some embodiments, the levels utilized in combination will be lowerthan those utilized individually.

The additional pharmaceutical agents include, but are not limited to,anti-proliferative agents, anti-cancer agents, cytotoxic agents,anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants,anti-bacterial agents, anti-viral agents, cardiovascular agents,cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents,contraceptive agents, and pain-relieving agents. In certain embodiments,the additional pharmaceutical agent is an anti-proliferative agent. Incertain embodiments, the additional pharmaceutical agent is ananti-cancer agent. In certain embodiments, the additional pharmaceuticalagent is an anti-viral agent. In certain embodiments, the additionalpharmaceutical agent is a binder or inhibitor of a protein kinase. Incertain embodiments, the additional pharmaceutical agent is selectedfrom the group consisting of epigenetic or transcriptional modulators(e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors(HDAC inhibitors), lysine methyltransferase inhibitors), antimitoticdrugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators(e.g., estrogen receptor modulators and androgen receptor modulators),cell signaling pathway inhibitors (e.g., tyrosine protein kinaseinhibitors), modulators of protein stability (e.g., proteasomeinhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoicacids, and other agents that promote differentiation. In certainembodiments, the compounds described herein or pharmaceuticalcompositions can be administered in combination with an anti-cancertherapy including, but not limited to, surgery, radiation therapy,transplantation (e.g., stem cell transplantation, bone marrowtransplantation), immunotherapy, and chemotherapy.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

Thus, in one aspect, provided are kits including a first containercomprising a compound or pharmaceutical composition described herein. Incertain embodiments, the kits are useful for treating a disease (e.g.,proliferative disease, hematological disease, neurological disease,painful condition, psychiatric disorder, or metabolic disorder) in asubject in need thereof. In certain embodiments, the kits are useful forpreventing a disease (e.g., proliferative disease, hematologicaldisease, neurological disease, painful condition, psychiatric disorder,or metabolic disorder) in a subject in need thereof. In certainembodiments, the kits are useful for reducing the risk of developing adisease (e.g., proliferative disease, hematological disease,neurological disease, painful condition, psychiatric disorder, ormetabolic disorder) in a subject in need thereof. In certainembodiments, the kits are useful for inhibiting the activity (e.g.,aberrant activity, such as increased activity) of a protein kinase in asubject or cell.

In certain embodiments, a kit described herein further includesinstructions for using the kit. A kit described herein may also includeinformation as required by a regulatory agency such as the U.S. Food andDrug Administration (FDA). In certain embodiments, the informationincluded in the kits is prescribing information. In certain embodiments,the kits and instructions provide for treating a disease (e.g.,proliferative disease, hematological disease, neurological disease,painful condition, psychiatric disorder, or metabolic disorder) in asubject in need thereof. In certain embodiments, the kits andinstructions provide for preventing a disease (e.g., proliferativedisease, hematological disease, neurological disease, painful condition,psychiatric disorder, or metabolic disorder) in a subject in needthereof. In certain embodiments, the kits and instructions provide forreducing the risk of developing a disease (e.g., proliferative disease,hematological disease, neurological disease, painful condition,psychiatric disorder, or metabolic disorder) in a subject in needthereof. In certain embodiments, the kits and instructions provide forinhibiting the activity (e.g., aberrant activity, such as increasedactivity) of a protein kinase in a subject or cell. A kit describedherein may include one or more additional pharmaceutical agentsdescribed herein as a separate composition.

Methods of Treatment and Uses

Compounds of the invention are useful for the treatment of diseases anddisorders associated with the androgen receptor. Such diseases includeproliferative disorders. In a particular embodiment, the proliferativedisorder is breast cancer. In another particular embodiment, theproliferative disorder is prostate cancer. For example, FIGS. 2A to 7Cdepict data showing that compounds of the invention stagnate cellproliferation in a variety of cell lines.

Provided herein is a method of modulating the expression of a gene,wherein the gene expression is mediated by an androgen receptor,comprising exposing a cell containing the gene and the androgen receptorto a compound of the invention. For example, FIGS. 10A to 10B show thatcompounds of the invention modulate AR-mediated gene expression.

Provided herein is a method of modulating the expression of a gene,wherein the gene expression is mediated by an androgen receptor,comprising contacting a cell containing the androgen receptor with acompound of the invention. See, for example, FIGS. 10A to 10B.

Also provided herein is a method of modulating the expression of a gene,wherein the gene expression is mediated by an androgen receptor,comprising exposing the androgen receptor to a compound of theinvention. See, for example, FIGS. 10A to 10B.

Also provided herein is a method of modulating the expression of a gene,wherein the gene expression is mediated by an androgen receptor,comprising contacting the androgen receptor with a compound of theinvention. See, for example, FIGS. 10A to 10B.

In an embodiment of the methods, the gene is selected from ACBD6, AKT1,ALG12, AP2A2, AQP12, BAG1, BAZ1B, BRCA1, CARKL, CDK1, CDK2, CDK9,CEP350, CHRM1, CLDN4, COX5B, CRELD2, DACH1, DDT, EFCAB6, FDZ9, FGF8,FOXO1, GAPDH, GNB2L1, GSK3B, GSTT2, HDAC1, HSP90AA1, HTATIP, JUN,KIAA1217, KIF1A, LHPP, LHX4, MAFG, MAGEA11, MAN2B2, MAP3K7IP1, MED1,MRFAP1, MUC6, MYST2, NCOA1, NCOA2, NCOA3, NCOA4, NCOA6, NCOR2, NONO,OAT, PA2G4, PAK6, PATZ1, PIAS2, PMEPA1, PRKCD, PRPF6, PSA, PTEN, PYCR1,QSCN6, RAD9A, RANBP9, RCHY1, RNF14, RNF4, SART3, SIRT1, SLC22A8,SCL22A6, SIRT7, SMAD3, SRC, SRY, STAT3, SVIL, SYNGR1, TGFB1I1, TMF1,TMPRSS2, TRIM68, TRPV1, TRPV3, UBE2I, UXT, WBSCR28, WBSCR27, and ZMIZ1.In an embodiment of the methods, the gene is AKT1.

Sequences of the androgen receptor gene products of interest hereinoften comprise or consist of sequences encoded by human androgenreceptor genes, although sequences of non-human mammalian homologs maybe used in certain embodiments. In general, the sequence of an androgenreceptor protein or androgen receptor RNA often comprises or consists ofa sequence of a human androgen receptor. In certain embodiments, thesequence of a gene product of an androgen receptor gene comprises orconsists of a naturally occurring sequence. It will be appreciated thata genetic locus may have more than one sequence or allele in apopulation of individuals. In some embodiments a naturally occurringsequence is a standard sequence. Unless otherwise indicated, a sequencelisted in the Reference Sequence (RefSeq) Database as a referencesequence for a protein that is referred to herein by a particular name,abbreviation, or symbol, is considered to be a “standard sequence.” If asequence has been updated subsequent to the time of the presentdisclosure a version current at the time of the present disclosure or anupdated version thereof may be used in certain embodiments. It will beappreciated that a genetic locus may have more than one sequence orallele in a population of individuals. In some embodiments a naturallyoccurring sequence differs from a standard sequence at one or more aminoacid positions. A naturally occurring polynucleotide or polypeptidewhose sequence differs from a standard sequence and that performs thenormal function(s) of the polynucleotide or polypeptide may be referredto as having a “normal sequence”.

In an embodiment of the methods, the androgen receptor is mammalian,e.g., human or murine. In an embodiment of the method, the androgenacceptor is an androgen receptor splice variant (AR-v) as describedherein. AR-vs include AR23, ARQ640X, AR-v1 (AR4), AR-v2, AR-v3(AR1/2/2b/AR6), AR-v4 (AR1/2/3/2b, AR5), AR-v5, AR-v6, AR-v7 (AR3),AR-v8, AR-v9, AR-v10, AR-v11, AR-v12 (ARV567es), AR-v13, AR-v14, AR-v15,AR-v16, AR-v18, AR8, and AR45.

In another embodiment, the androgen receptor is a variant having exons1, 2 and 3. In a particular embodiment, the AR-v is AR-v7. In anotherparticular embodiment, the androgen receptor is full-length androgenreceptor (AR-FL), e.g., human AR-FL.

In certain embodiments the sequence of an androgen receptor comprisesthe sequence of a naturally occurring androgen receptor protein or abiologically active variant thereof. A biologically active variant of anandrogen receptor protein may contain one or more additions,substitutions, and/or deletions relative to the sequence of a naturallyoccurring androgen receptor protein. In some embodiments the sequence ofan androgen receptor protein comprises a standard androgen receptorsequence. AR-FL is coded from eight exons and comprises four functionaldomains: an N-terminal domain (NTD), a DNA-binding domain (DBD), a hingeregion, and a C-terminal ligand binding domain (LBD). On the AR genelocus, exon 1 encodes the NTD, exons 2 and 3 encode the DBD, exon 4encodes the hinge region, and exons 5-8 encode the LBD. AR-FL isnormally 920 amino acids in length and has the following standard aminoacid sequence (GenBank and NCBI Reference Sequence Accession Number:NP_000035.2).

Sequences AR-FLMEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEIISVQVPKILSGKVKPIYFHTQ (SEQ ID NO: 1)AR23MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEEIPEERDSGNSLSGLSTLVFVLPGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEIISVQVPKILSGKVKPIYFHTQ (SEQ ID NO: 2)ARQ640XMEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKL (SEQ ID NO: 3)AR-v1 (AR4)MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGAAVVVSERILRVFGVSEWLP (SEQ ID NO: 4)AR-v2MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGAAVVVSERILRVFGVSEWLP (SEQ ID NO: 5) AR-v3 (AR1/2/2b/AR6)MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHTGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGAAVVVSERILRVFGVSEWLP (SEQ ID NO: 6) AR-v4 (AR1/2/3/2b AR5)MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGGFFRMNKLKESSDTNPKPYCMAAPMGLTENNRNRKKSYRETNLKAVSWPLNHTGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGAAVVVSERILRVFGVSEWLP (SEQ ID NO: 7)AR-v5MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGD (SEQ ID NO: 8)AR-v6MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGAGSRVS (SEQ ID NO: 9)AR-v7 (AR3)MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGEKFRVGNCKHLKMTRP (SEQ ID NO: 10)AR-v8MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGGFDNLCELSS (SEQ ID NO: 11)AR-v9MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGDNLPEQAAFWRHLHIFWDHVVKK (SEQ ID NO: 12)AR-v10MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTPSSGTNSVFLPHRDVVRTGCRSNSGYHSCSCEYHDYCFL(SEQ ID NO: 13) AR-v11MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGGKILFFLFLLLPLSPFSLIF (SEQ ID NO: 14)AR-v12 (ARV567es)MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPDCERAASVHF (SEQ ID NO: 15)AR-v13MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSINHT (SEQ ID NO: 16)AR-v14MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPTSCSRRFYQLTKLLDSVQPITPDAMYL (SEQ ID NO: 17) AR-v15MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSISPVKEQRDKKSRGHDTLYFTSSRQMNVESIKTQWN(SEQ ID NO: 18) AR-v16MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMITPDAMYL (SEQ ID NO: 19) AR-v18MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSISSRSHLMPCTCERGCSFVLEALSEQTRHLD (SEQ ID NO: 20)AR8MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRNTRRKRLWKLIIRSINSCICSPRETEVPVRQQK(SEQ ID NO: 21) AR45MILWLHSLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEIISVQVPKILSGKVKPIYFHTQ (SEQ ID NO: 22)

In another aspect, provided herein is a method of modulating androgenreceptor function comprising exposing the androgen receptor to acompound of the invention. In certain embodiments, the androgen receptoractivity is inhibited or antagonized.

In another aspect, provided herein is a method of modulating androgenreceptor function comprising contacting the androgen receptor with acompound of the invention. In an embodiment, the function of theandrogen receptor is inhibited. In an embodiment, the function of theandrogen receptor is antagonized.

In another aspect, provided herein is a method of treating a disorder ina subject in need of such treatment, wherein the disorder is associatedwith androgen receptor deregulation or dysregulation, comprisingadministering to the subject a compound of the invention, or apharmaceutical composition thereof. In an embodiment, the disorder iscancer. In another embodiment, the disorder is breast cancer. In anotherembodiment, the disorder is prostate cancer. In a particular embodiment,the prostate cancer is castration-resistant prostate cancer (CRPC). In aparticular embodiment, the subject is male. In another particularembodiment, the subject is female.

In an embodiment, the method further comprises administering anadditional therapeutic agent. In an embodiment, the additionaltherapeutic agent is administered simultaneously. In an embodiment, theadditional therapeutic agent is administered sequentially, e.g., priorto administration of a compound of the invention, or afteradministration of a compound of the invention.

In an embodiment, the second therapeutic agent is a chemotherapeuticagent.

In certain embodiments of the foregoing methods, the compound of theinvention is of Formula (I). In an embodiment, the compound of theinvention is selected from Formulae (IA)-(IF). In an embodiment, thecompound of the invention is of Formula (IF). In an embodiment, thecompound of the invention is selected from Formulae (IF-a), (IF-b),(IF-c), (IF-d), (IF-e) and pharmaceutically acceptable salts, solvates,hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, and prodrugs thereof.

In an embodiment, the compound of the invention is selected fromFormulae (IF-a3), (IF-b3), (IF-c3), (IF-d3), (IF-e3), (IF-a4), (IF-b4),(IF-c4), (IF-d4), (IF-e3), (IF-e4), and pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

In other embodiments of the foregoing methods, the compound of theinvention is of Formula (II). In an embodiment, the compound of theinvention is selected from Formulae (IIA), (IIB), (IIC), (IID), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof. In an embodiment, the compound of the invention isselected from Formulae (IIA-a), (IIA-b), (IIA-c), (IIA-d), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In another aspect, provided herein is the use of a compound of theinvention for modulating the expression of a gene, wherein the geneexpression is mediated by an androgen receptor.

In another aspect, provided herein is the use of a compound of theinvention for modulating androgen receptor function.

In another aspect, provided herein is the use of a compound of theinvention for treating a disorder in a subject, wherein the disorder isassociated with androgen receptor deregulation or dysregulation. In anembodiment, the disorder is cancer. In another embodiment, the disorderis prostate cancer. In a particular embodiment, the prostate cancer iscastration resistant prostate cancer (CRPC).

In certain embodiments of the foregoing uses, the compound of theinvention is used in combination with an additional therapeutic agent,e.g., a chemotherapeutic agent.

Identification of Androgen Receptor Modulators

Compounds of the invention can be evaluated by secondary binding assays(e.g., surface plasmon resonance (SPR), thermal shift, and calorimetry),functional assays, or phenotypic assays (e.g., qPCR). Secondary bindingassays may be used to determine whether or not the compound interactsdirectly with the target protein of interest (e.g., binds to the targetprotein) or to another protein in a complex (e.g., a member other thanthe target protein of interest in a multimeric complex comprising thetarget protein of interest), or to measure the binding affinities.

“Phenotypic assays” or “phenotypic screens” (used interchangeablyherein) are used to identify or confirm that a compound (e.g., smallmolecule, peptide, RNAi, etc.) alters the phenotype of a cell ororganism. A phenotype is any observable characteristic or trait (e.g.,morphology, development, biochemical properties, physiologicalproperties, etc.) or the composite thereof of an organism. An organism'sphenotype results from the expression of its genetic code, i.e., itsgenotype. An organism's phenotype may also be influenced byenvironmental factors.

The term “qPCR” refers to a quantitative polymerase chain reaction or areal-time polymerase chain reaction. qPCR techniques for amplifying anddetecting changes in concentration of a specific DNA or RNA sequence(e.g., amplicon) are well known in the art. A qPCR assay is usedquantitatively or semi-quantitatively (e.g., above or below a certainamount of DNA molecules) to measure gene expression in a cell, e.g., anLNCaP cell. LNCaP cells are androgen-sensitive human prostateadenocarcinoma cells. The qPCR assay can be used to quantitate DNAexpression levels in a cell, often with the use of fluorescentDNA-binding dyes or special probes that comprise a fluorophore attachedto one end and a quencher molecule attached to the opposite end.Normally, the fluorophore is covalently attached to the 5′-end of theoligonucleotide probe and the quencher is attached to the 3′-end of theoligonucleotide probe.

The oligonucleotide probe comprises a nucleotide sequence that iscomplementary to the gene of interest (e.g., gene whose expression levelis to be measured) that can hybridize (e.g., associate) to the DNAsequence comprising the gene of interest.

One example of a probe that is routinely used in the art is the TaqMan™probe. The TaqMan™ probe has 5′->3′ exonuclease activity and a donorfluorophore and quencher attached to the 5′-end and 3′-end,respectively. Probes of this type are routinely used in the art. ATaqMan™ probe can be used to measure the expression level of a gene ofinterest, e.g., the expression level of prostate specific antigen (PSA).The PSA expression level may be used as a readout for the activity levelof an androgen receptor or fragment thereof.

Another representative phenotypic assay is RT-PCR. The term “RT-PCR”refers to reverse-transcription polymerase chain reaction. RT-PCR may beused to qualitatively detect gene expression through creation ofcomplementary DNA (cDNA) transcripts from mRNA. RT-PCR is used to cloneexpressed genes by reverse transcribing (e.g., transcribing RNA to DNA)the RNA of interest into its DNA complement through the use of thereverse transcriptase enzyme. The cDNA is then amplified by traditionalPCR techniques, which are well known in the art.

Another representative phenotypic assay is quantitative RT-PCR. The term“quantitative RT-PCR” or “qRT-PCR” refers to a combination of the qPCRand RT-PCR techniques.

Compounds of the invention may also be identified via a reporter assay.Reporter assays are commonly used to study signaling pathways, geneexpression and regulation at the transcriptional level, and thestructure of regulatory elements. In general, a reporter assay comprisesa regulatory element of interest (e.g. promoter DNA) along with areporter gene (e.g., gene encoding a reporter protein) cloned into avector and transfected into cells. In certain embodiments, a reporter isa protein. In certain embodiments, a reporter is a protein with aneasily measureable activity. “Easily measureable activity” (or simply“activity”) can refer to any activity that can be measured throughmethods known in the art, such as fluorescence, enzymatic activitiesthat generate fluorescent or luminescent products, or indirectly withantibodies. The activity of the regulatory element can be directlymodulated by experimental conditions (e.g., introduction of a modulatorinto the cellular environment). Activity is directly correlated to theconcentration of reporter produced from the transcription of thereporter gene, i.e., transcription of the promoter leads to productionof the reporter, such that strong promoters produce more reporter andweak promoters produce less reporter. In certain embodiments, thereporter protein is luciferase. Luciferase is a generic term for a classof oxidative enzymes that produce bioluminescence, for example fireflyluciferase, Renilla luciferase, NanoLuc luciferase, bacterialluciferase, among others. In certain embodiments, the regulatory elementis a MMTV promoter.

In certain embodiments, the MMTV promoter and luciferase are encoded by(e.g., the DNA sequences are contained within) the same vector andtransfected into cells. Design of vectors and transfection of vectorsinto cells are methods well known in the art. See, e.g., Sambrook,Russell, and Sambrook, Molecular Cloning: A Laboratory Manual, 3^(rd)ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2001.

A “dual-reporter assay” is conceptually similar to the single reporterassay described above, and can correct for experimental variation (e.g.,cell number, transfection efficiency, etc.). In the case of adual-reporter assay, cells are transfected with two plasmids, the firstplasmid comprising the regulatory gene of interest and a first reporter,and the second plasmid comprising a constitutive promoter and a secondreporter, wherein the second reporter and the first reporter havebiologically distinct activities. The ratio of the first reporteractivity (e.g., controlled by the regulatory gene of interest) relativeto the second reporter activity (e.g., controlled by the constitutivepromoter) corrects for experimental variation. For example, adual-luciferase assay employs two luciferase reporter proteins that eachhave distinct bioluminescence signatures that can be easilydistinguished and measured. A compound may be submitted to a screencomprising a dual-luciferase assay, the dual-luciferase assay furthercomprising (i) a first vector comprising a first promoter and a firstreporter and (ii) a second vector comprising a second promoter and asecond reporter. In one embodiment, the first vector comprises a firstpromoter and a first reporter, wherein the first promoter is the MMTVpromoter and the first reporter is firefly luciferase, and the secondvector comprises a second promoter and a second reporter, wherein thesecond promoter is the CMV promoter and the second reporter is Renillaluciferase.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The examples describedin this application are offered to illustrate the methods, compositions,and systems provided herein and are not to be construed in any way aslimiting their scope.

Instrumentation: HRMS data was generated using a Bruker Daltonics APEXIV4.7 Tesla Fourier Transform Ion Cyclotron Resonance Mass Spectrometer(FT-ICR-MS). ¹H NMR data was generated using a VARIAN Inova-500 NMRSpectrometer with an Oxford Instruments Ltd. superconductingactively-shielded magnet, quad broadband RF (4 with Wave FormGeneration). Software: VNMR 6.1c, or using a Bruker AVANCE III-400 NMRSpectrometer with a SpectroSpin superconducting magnet. Software:TopSpin 3.1.

In the assays, probes for KLK3 (PSA gene) and GAPDH (cell count control)were used with the SingleShot™ Probes Kit for Cell Lysis and RT-qPCRfrom BioRad.

General Synthesis Procedures

Example 1. General Synthesis of Compounds of Formula (I)

3-Acetoxybenzoic acid was dissolved in DCM (0.4 M) and cooled to 0° C.in a dry and argon flushed reaction flask. Catalytic DMF (2 drops) wasadded to the mixture followed by dropwise addition of oxalyl chloride(3.0 equiv.). After consumption of the starting material as determinedby TLC, the reaction was concentrated under reduced pressure. Residualwater was azeotroped 3 times by the addition of toluene and subsequentevaporation. The intermediate acid chloride was then dried on thehigh-vac for 1 hour. The intermediate acid chloride was flushed withargon, dissolved in DCM (0.2 M), and cooled to 0° C. After the additionof TEA (4.0 equiv.), the respective amine (2.0 equiv.) was diluted ineither THF or DCM (2.0 M) and added slowly to the suspended acidchloride. The reaction was slowly warmed to room temperature and allowedto react until TLC indicated the reaction complete. Aqueous HCl (1.0 M)was added and the mixture was stirred for 1 h. After extraction with DCMthe combined organic layers were subsequently treated with saturatedaqueous NaHCO₃, washed with brine, and dried over MgSO₄. The resultantsolution was concentrated and purified via silica gel columnchromatography (EtOAc:Hex) to give the desired acetoxy benzamide (37-59%yield).

To a solution of acetoxybenzamide (1.0 equiv.) in THF (0.1 M) was addedaqueous lithium hydroxide (13.0 equiv., 4.6 N) at room temperature.After 2 hours, the reaction was deemed complete by TLC. The solution wasneutralized with HCl (1.0 M) to an approximate pH of 6 and subsequentlyconcentrated under reduced pressure to remove THF. The resultant aqueoussolution was extracted 3 times with DCM, whereupon the combined organiclayers were washed with brine and dried over anhydrous Na₂SO₄. Afterconcentration, the material was purified via silica gel columnchromatography (EtOAc:Hex) to give the desired product (95% yield).

In a dry and argon flushed 20 dram vial the starting hydroxybenzamide(1.0 equiv.) was dissolved in DMF (0.07 M). The tosylatedhydroxy-acylpiperidine (1.5 equiv.) and K₂CO₃ (2.0 equiv.) weresubsequently added. The reaction vessel was sealed and the mixtureheated to 80° C. and stirred for 12 h after which the conversion ofstarting materials was incomplete. Regardless, the solution was cooledto room temperature and poured into H₂O. The solution was extracted withEtOAc (3 times), washed with brine, and dried over anhydrous MgSO₄.After concentration, the material was purified via silica gel columnchromatography (EtOAc:Hex) to give the desired product (26-63% yield).

4-Hydroxypiperidine was placed into a dried and argon flushed reactionflask. DCM (1.0 M) and TEA (1.1 equiv.) were added to the solution atroom temperature. The mixture was then cooled to −60° C. before the acylchloride was added dropwise. Once all the components were added, thereaction was slowly warmed to room temperature. After 1.5 hours, thereaction was deemed complete by TLC and the reaction was worked up byadding aqueous HCl (1.0 M). After extraction with DCM the combinedorganic layers were treated with saturated aqueous NaHCO₃, washed withbrine, and dried over MgSO₄. The resultant solution was concentrated andpurified via silica gel column chromatography (EtOAc:Hex) to give thedesired 4-hydroxy acylpiperidine (58-92% yield).

In a dried and argon flushed reaction vessel, 4-hydroxy acylpiperidine(1.0 equiv.) was dissolved in DCM (0.4 M). TEA (1.5 equiv.), DMAP (0.05equiv.), and tosyl chloride (1.2 equiv.) were then added sequentially.The reaction was left at room temperature for 12 hours whereupon TLCrevealed consumption of starting material. Saturated aqueous NaHCO₃ wasadded and the reaction was extracted 3 times with DCM. The organic layerwas neutralized with saturated NaHCO₃, washed with brine, and dried overMgSO₄. The resultant solution was concentrated and purified via silicagel column chromatography (EtOAc:Hex) to give the desired 4-hydroxyacylpiperidine (74-99% yield).

In a dry and argon flushed 20 dram vial the starting methylhydroxybenzoate (1.0 equiv.) was dissolved in DMF (0.07 M). Thetosylated hydroxy-acylpiperidine (1.5 equiv.) and K₂CO₃ (2.0 equiv.)were subsequently added. The reaction vessel was sealed and the mixtureheated to 80° C. and stirred for 12 h after which the conversion ofstarting materials was incomplete. Regardless, the solution was cooledto room temperature and poured into H₂O. The solution was extracted withEtOAc (3 times), washed with brine, and dried over anhydrous MgSO₄.After concentration, the material was purified via column chromatography(EtOAc:Hx) to give the desired product (55-65% yield).

To a solution of starting methyl ester (1.0 equiv.) in THF (0.1 M) wasadded aqueous lithium hydroxide (13.0 equiv., 4.6 N). The mixture washeated to 65° C. and stirred for 2 hours. After consumption of startingmaterial as determined by TLC, the solution was concentrated underreduced pressure to remove THF and subsequently acidified withconcentrated HCl until the title carboxylic acid precipitated fromsolution. The precipitate was washed with cold H₂O, and dried on thehigh-vac overnight (70-93% yield).

In a dried and argon flushed reaction flask, the respective carboxylicacid was dissolved in DMF (0.2 M). Subsequently, the respective amine(1.5 equiv.) and DIPEA (5.0 equiv.) were added. The mixture was allowedto stir for 5 min whereupon HATU (2.0 equiv.) was added. The combinedmixture was stirred at room temperature for 16 hours or until indicatedcomplete by TLC. Upon consumption of starting material, the reaction wasdiluted with H₂O and extracted with EtOAc. The combined organic layerswere washed with brine and dried over anhydrous MgSO₄ before beingconcentrated and purified via silica gel column chromatography(EtOAc:Hex) to afford the desired benzamide (30-84% yield).

Example 2. General Synthesis of Compounds of Formula (II)

In a sealed tube previously dried and flushed with argon, methyl4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (1.0 equiv.) wasdissolved in 1,4-dioxane (0.5 M). The respective amine (1.5 equiv.) andpara-toluenesulfonic acid (0.05 equiv.) were subsequently added. Thevessel was sealed and the reaction mixture heated to 120° C. and stirredfor 12 hours. Upon completion as indicated by TLC, the solution wasconcentrated under reduced pressure and the residuals were reconstitutedin EtOAc and aqueous HCl (1.0 M). The biphasic mixture was separated andthe aqueous layer was further extracted with EtOAc. The combined organiclayers were washed with brine, and dried over MgSO₄. Concentration andpurification via silica gel column chromatography (EtOAc:Hex) gave thedesired product (18-44% yield).

To a solution of methyl4-(amine-substituted)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (1.0equiv.) in THF (0.1 M) was added lithium hydroxide solution (13.0equiv., 4.6 N). The mixture was heated to 65° C. for 2 hours. Afterconsumption of starting material as determined by TLC, the solution wasconcentrated under reduced pressure to remove THF and was subsequentlyacidified with concentrated HCl until the title carboxylic acidprecipitated from the solution. The precipitate was filtered, washedwith cold H₂O, and dried on high-vac overnight (20-70% yield).

In a reaction flask previously dried and flushed with argon, therespective carboxylic acid was dissolved in DMF (0.2 M) before thesubsequent addition of N-methyl-1-(5-quinolinyl)methanaminehydrochloride (1.5 equiv.) and DIPEA (5.0 equiv.). The mixture wasallowed to stir for 5 min whereupon HATU (2.0 equiv.) was added. Thecombined mixture was stirred at room temperature for 6 hours and wasdeemed complete by TLC. The reaction mixture was poured directly intowater, extracted with EtOAc, washed with brine, and dried over anhydrousMgSO₄. The solution was then concentrated and purified via silica gelcolumn chromatography to afford the desired quinolinylmethanamide(38-87% yield).

In a reaction flask previously dried and flushed with argon, therespective carboxylic acid was dissolved in DMF (0.2 M) before thesubsequent addition of 2-naphthylamine (1.5 equiv.) and DIPEA (5.0equiv.). The mixture was allowed to stir for 5 min whereupon HATU (2.0equiv.) was added. The combined mixture was stirred at room temperaturefor 6 hours or until indicated complete by TLC. Upon consumption ofstarting material, the reaction was diluted with H2O and extracted withEtOAc. The combined organic layers were washed with brine and dried overanhydrous MgSO₄. The solvent was removed under reduced pressure and thecrude was purified via silica gel column chromatography to afford thedesired 2-naphthylamide (36% yield).

Example 3. Experimental Data

All compounds were evaluated in a reporter gene assay (22Rv1 cell linelentiviral transduced with CMV-firefly luciferase) to monitortranscriptional effects and two cell viability assays (Cell-titer blue;PC3 cell line, an AR insensitive cell line, and LNCaP cell line, an ARsensitive cell line). The compounds were also monitored for aggregation.

TABLE 3 Compound Data. Reporter PC3 CTB LNCaP CTB Solubility CompoundIC50 (μM) IC50 (μM) IC50 (μM) (mM) HRMS I-3 ~24.64 3558 16.67 25437.2786 [M + H] I-4 ~25.2 33449 24.32 25 451.2958 [M + H]; 901.5752[2M + H] I-5 ~25.22 0 24.64 25 423.2629 [M + H] I-6 ~24.95 2.616E+148.199 25 445.2476 [M + H]; 467.2283 [M + Na] I-7 ~25.85 52.38 25459.2657 [M + H] I-8 21.92 70.51 25 437.2055 [M + H]; 873.4037 [2M + H]I-9 354.9 25 446.2447 [M + H] I-10  2.928E+40 25 409.2468 [M + H];431.2293 [M + Na] I-11 28.26 6.73418E+13 25 395.2334 [M + H] I-12 I-13172 25 437.2807 [M + H] I-14  3.418E+18 25 451.2958 [M + H] I-15 I-16I-17 5.208 18.4 25 423.1901 [M + H] I-18 ~24.35 41.22 25 409.2491 [M +H] I-19 25 300.1594 [M + H]; 599.3134 [2M + H] I-20 25 258.1490 [M + H]I-21 341.5 25 467.3268 [M + H] I-22 3578 6.25 507.2396 [M + H];1013.4673 [2M + H] I-23 ~25.49 1020 25 409.2496 [M + H] I-24 20.43 165312.5 444.2293 [M + H] I-25 387.8 25 409.2467 [M + H]; 431.2281 [M + Na]I-26 340.9 222 25 407.2336 [M + H] I-27 49.92 28.52 12.5 415.2022 [M +H] I-28 176 698.5 25 399.1482 [M + H] I-29 25.13 25 407.2337 [M + H];429.2159 [M + Na] I-30 135.8 25 365.1876 [M + H]; 387.1693 [M + Na] I-31166 62.65 25 379.2022 [M + H]; 401.1838 [M + Na] I-32 100.8 79.17 25399.2652 [M + H]; 421.2466 [M + Na] I-33 423.2634 [M + H]; 445.2446 [M +Na] I-34 ~27.86 55.78 28.84 12.5 425.2801 [M + H] I-35 31.47 26.52 25423.2656 [M + H] I-36 80.48 25 439.2599 [M + H] I-37 1151 286882 25 I-381889  1.338E+18 12.5 I-39 93.88 396.8 25 437.2033 [M + H] I-40 90.27120.3 25 446.2441 [M + H] II-3 3207 492.9 25 II-4 9.631 10.72 25474.2305 [M + H]; 947.4574 [2M + H] II-5 2.362 781.9 8.09 25 484.2152[M + H]; 967.4290 [2M + H] II-6 8.287 1680 14.08 25 484.2145 [M + H];967.4367 [2M + H] II-7 68.23 25 441.1743 [M + H]

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

REFERENCES

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What is claimed is:
 1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: L₁ is absent, oris optionally substituted C₁₋₆ aliphatic, or optionally substituted C₁₋₆heteroaliphatic; L₂ is absent, or is optionally substituted C₁₋₆aliphatic, or optionally substituted C₁₋₆ heteroaliphatic; X is —O—, —S—or —N(R)—; R is hydrogen, or optionally substituted alkyl; Q₁, Q₂, andQ₃, independently, are ═N— or ═C(R₁)—; R₁ is hydrogen, halogen, —CN,—NO₂, —Ra, —OH, —OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)N(R^(a))₂,—NH₂, —N(R^(a))₂, —NC(O)R^(a), —NC(O)OR^(a), or —NC(O)N(R^(a))₂; whereineach occurrence of R^(a), independently, is optionally substitutedaliphatic, optionally substituted heteroaliphatic, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl; R₂ is optionallysubstituted carbocyclyl, optionally substituted heterocyclyl whereineach heteroatom is independently selected from nitrogen and oxygen,optionally substituted aryl, or optionally substituted heteroaryl; R₃ isoptionally substituted alkyl, or optionally substituted cycloalkyl; R₄is hydrogen or optionally substituted alkyl; and R₅ is optionallysubstituted aryl or optionally substituted heteroaryl.
 2. The compoundof claim 1, having the structure selected from Formulae (IIA), (IIB),(IIC), and (IID), and pharmaceutically acceptable salts thereof:


3. The compound of claim 1, having the structure of Formula (IIA-a):


4. The compound of claim 1, having the structure of Formula (IIA-b):


5. The compound of claim 1, having the structure of Formula (IIA-c):


6. The compound of claim 1, having the structure of Formula (IIA-d):


7. The compound of claim 1, selected from the compounds of Table 2, andpharmaceutically acceptable salts thereof.
 8. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier or diluent.
 9. A method of modulating the expressionof a gene, wherein the gene expression is mediated by an androgenreceptor, comprising exposing the androgen receptor to a compound ofclaim
 1. 10. A method of modulating androgen receptor function,comprising exposing the androgen receptor to a compound of claim
 1. 11.The method of claim 9, wherein the gene is AKT1.
 12. The method of claim9, wherein the androgen acceptor is an androgen receptor splice variant(AR-v).
 13. The method of claim 12, wherein the AR-v is AR-v7.
 14. Amethod of treating prostate cancer in a subject in need of suchtreatment, comprising administering to the subject a compound ofclaim
 1. 15. The compound of claim 2, having the structure of Formula(IIA), or a pharmaceutically acceptable salt thereof.
 16. The compoundof claim 1, wherein R₁ is hydrogen, optionally substituted aliphatic,optionally substituted amino, optionally substituted aryl, optionallysubstituted heterocyclyl, or optionally substituted heteroaryl.
 17. Thecompound of claim 1, wherein R₂ is optionally substituted C₅₋₁₀cycloaliphatic, optionally substituted C₆₋₁₀ aryl, or optionallysubstituted C₆₋₁₀ heteroaryl.
 18. The compound of claim 1, wherein R₃ isC₁₋₆ alkyl.
 19. The compound of claim 1, wherein R₄ is C₁₋₆ alkyl. 20.The compound of claim 1, wherein R₅ is optionally substitutedheteroaryl.